Difficulty: Advanced | Prerequisites: Nomenclature, stereoisomerism, acid-base concepts, orbital theory
This is the core of Organic Chemistry I: knowing which reagent transforms an alkene or alkyne into which product, with what stereochemistry. You need to recognise reagents on sight, predict regiochemistry (Markovnikov vs. anti-Markovnikov) and stereochemistry (syn vs. anti addition, racemic vs. enantiospecific), draw full mechanisms for key reactions, and chain reactions together into multi-step syntheses.
Markovnikov addition
In the addition of HX to an alkene, the hydrogen adds to the less substituted carbon and the halide to the more substituted carbon, forming the more stable (more substituted) carbocation intermediate.
In simple terms, "the rich get richer" : the carbon that already has more hydrogens gets the new hydrogen.
Anti-Markovnikov addition
The opposite regiochemistry: the hydrogen ends up on the more substituted carbon and the other group on the less substituted carbon. This occurs under radical conditions (HBr + peroxides) or with hydroboration-oxidation (BH₃ then H₂O₂/NaOH).
Syn addition
Both new groups add to the same face of the double bond. Examples: catalytic hydrogenation (H₂/Pd), hydroboration, Diels-Alder cycloaddition.
Anti addition
The two new groups add to opposite faces of the double bond. Examples: bromohydrin formation (Br₂/H₂O), halogenation via a cyclic halonium ion intermediate.
Carbocation
A carbon bearing a positive charge (three bonds, empty p orbital). Stability order: 3° > 2° > 1° > methyl. Carbocation stability drives Markovnikov selectivity.
Halonium ion
A cyclic, positively charged intermediate formed when a halogen (Br₂ or Cl₂) reacts with a double bond. The bridged ring blocks one face, forcing the nucleophile to attack from the opposite side (anti addition).
SN2 (bimolecular nucleophilic substitution)
A one-step mechanism where the nucleophile attacks the electrophilic carbon from the back side as the leaving group departs. Rate depends on both nucleophile and substrate concentration. Proceeds with inversion of configuration (Walden inversion). Favoured by primary substrates, strong nucleophiles and polar aprotic solvents.
SN1 (unimolecular nucleophilic substitution)
A two-step mechanism: the leaving group departs first to form a carbocation, then the nucleophile attacks. Rate depends only on substrate concentration. Produces racemisation (attack from both faces of the planar carbocation). Favoured by tertiary substrates, weak nucleophiles and polar protic solvents.
E2 elimination
A one-step mechanism where a strong base removes a proton while the leaving group departs simultaneously, forming a double bond. Requires anti-periplanar geometry of the H and leaving group.
Radical chain reaction
A reaction proceeding through radical intermediates, with initiation (radical formation), propagation (chain-carrying steps) and termination (radical coupling) stages.
Li, NH₃ (dissolving-metal reduction): converts an internal alkyne to a trans (E) alkene via radical anion intermediates.
H₂, Lindlar catalyst: converts an internal alkyne to a cis (Z) alkene. Lindlar catalyst is "poisoned" Pd so it stops at the alkene stage.
NaNH₂, then R-X (alkylide alkylation): deprotonates a terminal alkyne to form the acetylide anion, which then does SN2 on an alkyl halide. Used to extend carbon chains. Only works with primary (and methyl) R-X because SN2 needs unhindered substrates.
H₂, Pd/C: fully reduces an alkyne (or alkene) to an alkane. Both pi bonds hydrogenated.
HBr (no peroxides): Markovnikov addition. H goes to the less substituted carbon; Br to the more substituted.
HBr, peroxides: anti-Markovnikov addition via radical mechanism. Br ends up on the less substituted carbon.
HBr, excess (to alkynes): adds two equivalents of HBr across a triple bond, both following Markovnikov, giving a geminal dibromide.
HCl, excess (to alkynes): same idea as HBr excess, gives a geminal dichloride.
Br₂, H₂O (bromohydrin): anti addition via bromonium ion; water acts as nucleophile. Gives a bromohydrin (Br and OH on adjacent carbons, anti to each other). The OH attaches to the more substituted carbon (Markovnikov-like opening of the bromonium ion).
m-CPBA (meta-chloroperoxybenzoic acid): epoxidation. Converts an alkene to an epoxide (oxirane) with retention of alkene geometry (syn addition of the oxygen). Racemic if the alkene is not already chiral.
BH₃, then H₂O₂/NaOH (hydroboration-oxidation): anti-Markovnikov, syn addition of water across the double bond. The -OH ends up on the less substituted carbon.
H₂O, H₂SO₄ (acid-catalysed hydration): Markovnikov addition of water. The -OH goes to the more substituted carbon.
H₂O, H₂SO₄, HgSO₄ (oxymercuration of alkynes): Markovnikov addition of water to an alkyne, producing a ketone (via enol tautomerisation). On a terminal alkyne this gives a methyl ketone.
O₃, then Zn/H₂O (ozonolysis, reductive workup): cleaves a double bond entirely, converting each end into an aldehyde (from -CH=) or a ketone (from -CR=). If the alkene is part of a ring, the ring opens to a dicarbonyl.
Br₂, light (or Cl₂, light): radical halogenation at an allylic or benzylic position (not addition to a double bond). Selectivity: Br₂ is more selective for the more substituted (more stable radical) position.
KCN, DMF: SN2 with cyanide as nucleophile in a polar aprotic solvent. Replaces a leaving group with -CN.
NaCl, DMF: SN2 with chloride nucleophile.
NaN₃, DMF: SN2 with azide nucleophile. Inverts configuration.
NaOEt, EtOH: E2 elimination with ethoxide as a strong, moderately bulky base. Gives the more substituted (Zaitsev) alkene.
KOt-Bu: E2 elimination with a bulky base. Favours the less substituted (Hofmann) alkene due to steric approach control.
PBr₃: converts an alcohol (-OH) to an alkyl bromide (-Br) with inversion of configuration (SN2-like mechanism at phosphorus, then SN2 displacement). The key reagent when you need to turn a secondary alcohol into a bromide for subsequent nucleophilic substitution.
H₂SO₄, heat: acid-catalysed dehydration of an alcohol to form an alkene (E1 for 3° and 2° alcohols).
Diels-Alder reactions use a conjugated diene and a dienophile (an alkene or alkyne bearing electron-withdrawing groups). The product is a six-membered ring. Common dienophiles include maleic anhydride and alkenes with -CN, -COOR or -COR groups. The stereochemistry is suprafacial on both components (syn addition), and endo products are kinetically favoured.
Markovnikov: HX addition (ionic), acid-catalysed hydration, oxymercuration. The electrophilic H attaches to the less substituted carbon; the nucleophile (X, OH) goes to the more substituted carbon via the more stable carbocation.
Anti-Markovnikov: HBr with peroxides (radical mechanism), hydroboration-oxidation. The nucleophilic group ends up on the less substituted carbon.
Syn addition (both groups same face): H₂/Pd (or Lindlar), hydroboration, epoxidation (the O atom bridges the same face), Diels-Alder.
Anti addition (groups on opposite faces): Br₂ addition (via bromonium ion), Br₂/H₂O (bromohydrin), ring-opening of epoxides under acidic conditions.
Racemic mixture (equal amounts of both enantiomers): forms whenever a new stereocentre is created and there is no chiral influence. For example, HBr addition to a symmetric alkene gives a racemic product. Bromohydrin formation on a cyclic alkene gives anti addition but typically as a racemic pair (+ enantiomer).
Inversion of configuration: SN2 reactions. The nucleophile attacks from 180° opposite the leaving group, flipping the stereocentre.
Retention of configuration: hydroboration gives syn addition (retention relative to the alkene face), and reactions that proceed through a concerted mechanism without a free carbocation.
Terminal alkyne + NaNH₂ then CH₃I: the base removes the terminal H, then the acetylide does SN2 on methyl iodide to give an internal alkyne extended by one carbon (a methyl group).
Internal alkyne + H₂/Pd/C: full reduction to the alkane.
Internal alkyne + H₂O/H₂SO₄/HgSO₄: Markovnikov hydration giving a ketone.
Cyclopentene + Br₂/H₂O: anti addition of Br and OH, giving a trans-bromohydrin (+ enantiomer).
Diene + dienophile with EWG (e.g., maleic anhydride or trans-disubstituted alkene with -CN groups): Diels-Alder cycloaddition, syn/syn, endo selectivity.
Alkene + O₃ then Zn/H₂O: cleavage to give two carbonyl compounds (aldehydes and/or ketones depending on substitution).
Allylic benzylic substrate + Br₂/light: radical substitution at the benzylic position.
Secondary alkyl bromide + NaOEt/EtOH: E2 elimination giving the Zaitsev alkene (more substituted).
Secondary alkyl bromide + NaN₃/DMF: SN2, inversion of configuration, azide product.
When an allylic chloride is treated with methanol (a weak nucleophile, polar protic solvent), the mechanism proceeds as SN1:
Step 1: The C-Cl bond breaks heterolytically. Chloride departs as the leaving group, generating an allylic carbocation.
Step 2 (resonance): The allylic carbocation has two resonance forms, with the positive charge delocalised across two carbons. Draw both resonance contributors with a double-headed arrow between them.
Step 3: Methanol (the nucleophile/solvent) attacks one of the carbocation carbons. Because the carbocation is planar, attack can occur from either face.
Step 4: Loss of a proton from the oxonium ion gives the methyl ether product. Chloride (or another base) can abstract this proton. HCl is the byproduct.
Key features: no inversion requirement (racemisation at a stereocentre), resonance-stabilised carbocation intermediate, solvent acts as nucleophile.
When an alkane (or a benzylic/allylic substrate) is treated with Br₂ and light (or heat), bromination occurs via a radical chain mechanism:
Initiation: Light (hv) causes homolytic cleavage of the Br-Br bond, generating two bromine radicals (Br•). Curved fishhook (single-barbed) arrows show one electron going to each bromine.
Propagation step 1: A bromine radical abstracts a hydrogen atom from the substrate (from the weakest C-H bond, typically at the most substituted position for selectivity reasons). This produces HBr and a carbon radical. Fishhook arrows: one from the C-H bond to H (going to Br•) and one from C-H to carbon.
Propagation step 2: The carbon radical reacts with another Br₂ molecule. One bromine atom bonds to the radical carbon; the other becomes a new Br• radical that continues the chain. Fishhook arrows: one electron from the radical carbon to one Br, and the Br-Br bond breaks homolytically.
Termination: any two radicals combine (Br• + Br•, R• + Br•, or R• + R•), ending the chain.
Bromine is more selective than chlorine: it preferentially abstracts from the most substituted position because the transition state resembles the more stable radical intermediate.
This is a two-step sequence tested in the miscellaneous section:
Step 1: PBr₃ converts the alcohol to an alkyl bromide with inversion of configuration (the OH is replaced by Br via an SN2-type process).
Step 2: NaSH in DMF (polar aprotic solvent) does SN2 on the alkyl bromide, inverting configuration again. Two inversions = net retention of the original alcohol's configuration.
This is why PBr₃ then NaSH/DMF is preferred over direct substitution (NaSH/DMF on the alcohol directly would not work because -OH is a poor leaving group) and over TsCl/Py then NaSH (which also gives net retention but is a less clean conversion for this substrate).
Work backwards from the target molecule. Identify which bonds need to form and which functional groups need to change. Then select reagents that accomplish each step with the correct regiochemistry and stereochemistry.
Target: a primary alcohol on the carbon chain attached to benzene, one carbon away from the ring.
Step 1: Br₂/light performs radical benzylic bromination on ethylbenzene, placing Br at the benzylic position.
Step 2: NaOEt/EtOH performs E2 elimination on the benzylic bromide, giving styrene (phenylethylene, the alkene).
Step 3: BH₃ then H₂O₂/NaOH performs hydroboration-oxidation on styrene, adding -OH to the terminal (less substituted) carbon with anti-Markovnikov selectivity and syn stereochemistry. The product is 2-phenylethan-1-ol.
This three-step sequence demonstrates a common pattern: install a leaving group, eliminate to form an alkene, then add across the alkene with the desired regiochemistry.
If you need anti-Markovnikov addition of -OH, use hydroboration-oxidation.
If you need Markovnikov addition of -OH, use acid-catalysed hydration or oxymercuration-demercuration.
If you need to extend a carbon chain, use an acetylide alkylation (NaNH₂ then R-X on a terminal alkyne).
If you need to convert an alkyne to a cis alkene, use H₂/Lindlar. For a trans alkene, use Li/NH₃.
If you need to break a double bond entirely, use ozonolysis (O₃ then Zn/H₂O).
Students often confuse HBr (ionic, Markovnikov) with HBr/peroxides (radical, anti-Markovnikov). The presence of peroxides flips the regiochemistry. This only works for HBr, not HCl or HI.
Students sometimes think hydroboration-oxidation gives Markovnikov products. It gives anti-Markovnikov addition of -OH (the -OH goes to the less substituted carbon) with syn stereochemistry.
Students frequently forget that ozonolysis with Zn/H₂O (reductive workup) gives aldehydes and ketones, while ozonolysis with H₂O₂ (oxidative workup) converts any aldehyde to a carboxylic acid.
Students often draw SN2 on a tertiary substrate. SN2 does not proceed on 3° carbons due to steric hindrance. Tertiary substrates undergo SN1 or E1/E2 instead.
Students sometimes assume that all addition reactions give racemic products. This is true only when a new stereocentre is formed without chiral influence. If the starting material is already chiral or the addition is stereospecific (e.g., anti addition via a cyclic intermediate), the stereochemical outcome is determined.
⚠️ Reagent identification is the single highest-weighted problem type on many Organic Chemistry I finals. You will be shown a starting material, a product and a blank for the reagent, or a starting material, a reagent and a blank for the product.
⚠️ Stereochemistry notation matters. If stereoisomers can form, you must write "+ enantiomer" or "(+/-)" next to the product. Omitting this loses marks.
⚠️ Mechanism questions require curved arrows showing electron flow. For ionic mechanisms, use full (double-barbed) arrows. For radical mechanisms, use fishhook (single-barbed) arrows. Show every intermediate, including resonance forms of carbocations.
⚠️ Synthesis questions test your ability to chain 2 to 4 reactions together. Work backwards from the product.
⚠️ SN2 rate ranking: the rate depends on steric hindrance at the electrophilic carbon. Methyl > primary > secondary; tertiary does not undergo SN2. Neopentyl-type substrates (primary but with heavy branching at the beta carbon) are also very slow.
True or false: HBr/peroxides adds Br to the more substituted carbon. (False: peroxides give anti-Markovnikov, so Br goes to the less substituted carbon.)
Fill in the blank: Hydroboration-oxidation gives ________ addition with ________ regiochemistry. (Syn addition, anti-Markovnikov.)
True or false: SN2 proceeds with retention of configuration. (False: SN2 proceeds with inversion.)
Fill in the blank: Ozonolysis followed by Zn/H₂O converts a double bond into two ________ groups. (Carbonyl, i.e., aldehydes and/or ketones.)
True or false: Br₂/light performs addition across a double bond. (False: it performs radical substitution at an allylic or benzylic position.)
Q: An internal alkyne is treated with Li/NH₃. What is the product and its geometry?
A: A trans (E) alkene. Dissolving-metal reduction gives the anti addition product.
Q: Cyclohexene is treated with Br₂/H₂O. Draw the product and specify stereochemistry.
A: Trans-2-bromocyclohexan-1-ol (a bromohydrin). Br and OH are anti to each other. The product forms as a racemic pair (+ enantiomer).
Q: What reagent converts an alkene into an epoxide?
A: m-CPBA (meta-chloroperoxybenzoic acid). The oxygen is delivered in a syn fashion, and if the alkene is not chiral the epoxide forms as a racemic mixture.
Q: You need to convert ethylbenzene into 2-phenylethan-1-ol. Propose a synthesis.
A: (1) Br₂/light (radical benzylic bromination), (2) NaOEt/EtOH (E2 elimination to styrene), (3) BH₃ then H₂O₂/NaOH (hydroboration-oxidation, anti-Markovnikov -OH addition).
Q: A secondary alcohol with defined stereochemistry must be converted to the corresponding thiol with retention of configuration. Which reagent sequence works best?
A: PBr₃ (inverts configuration to give the alkyl bromide), then NaSH/DMF (SN2, inverts again). Two inversions give net retention.
Q: Rank the following substrates from slowest to fastest for SN2: I (neopentyl-type chloride), II (secondary chloride), III (primary chloride).
A: III < I < II is incorrect. The correct order slow to fast is III (neopentyl, extremely hindered) < I < II, or more precisely as given in the exam key: III < I < II.
Reaction mechanisms connect directly to kinetics and thermodynamics: whether a reaction is SN1 or SN2 determines the rate law, and whether it is kinetically or thermodynamically controlled determines the product. Stereochemistry outcomes (syn/anti, Markovnikov/anti-Markovnikov) depend on the mechanism, so understanding the mechanism is not optional for predicting products. Multi-step synthesis draws on every reaction and every selectivity rule in the course, making it the capstone skill.
Alkene reactions, alkyne reactions, reagent identification, Markovnikov, anti-Markovnikov, syn addition, anti addition, hydroboration-oxidation, BH3 H2O2 NaOH, m-CPBA epoxidation, ozonolysis, bromohydrin, Br2 H2O, HBr peroxides, radical addition, radical halogenation, Br2 light, SN1, SN2, E2, E1, nucleophilic substitution, elimination, Zaitsev rule, Hofmann product, KOtBu, NaOEt, Lindlar catalyst, dissolving metal reduction, Li NH3, PBr3, reaction mechanism, curved arrows, carbocation, bromonium ion, racemic mixture, enantiomer, inversion of configuration, Diels-Alder, synthesis, retrosynthesis, Organic Chemistry I, CHEM 2301, UMN