Difficulty: Intermediate | Prerequisites: Alkene addition reactions, stereochemistry (syn/anti, cis/trans), functional group identification
This set of reactions lets you build oxygen-containing functional groups onto alkenes (epoxides, diols), break double bonds apart into carbonyls (ozonolysis, KMnO4), form three-membered carbon rings (cyclopropanes), and use carbon-metal bonds (Grignard, organolithium, Gilman reagents) to build new carbon-carbon frameworks. Together with the addition reactions from the first set of notes, these give you the full synthetic toolkit for alkene and alkyne transformations.
Epoxide (oxirane)
A three-membered ring containing one oxygen atom and two carbon atoms. Formed by syn addition of an oxygen atom across a double bond. The ring is strained and therefore highly reactive toward nucleophilic ring-opening.
Think of it as a tiny, tight oxygen bridge sitting on one face of what used to be the double bond.
MCPBA (meta-chloroperoxybenzoic acid)
A peroxyacid reagent used to convert alkenes to epoxides. It delivers a single oxygen atom to the same face of the double bond (syn addition).
In simple terms, MCPBA is the go-to reagent for making an epoxide from an alkene.
Glycol (1,2-diol / vicinal diol)
A compound with two hydroxyl groups on adjacent carbons. Can be formed with either cis or trans relative stereochemistry depending on the reagent.
Think of it as two OH groups sitting side by side on neighbouring carbons.
Ozonolysis
Cleavage of a carbon-carbon double bond using ozone (O3), followed by a reductive workup (Zn, H3O+). Splits the alkene into two carbonyl fragments (aldehydes and/or ketones). Hydrogens on the original double bond remain as C-H in the products.
In simple terms, ozonolysis cuts the double bond in two and caps each end with an oxygen.
Oxidative cleavage (KMnO4)
Cleavage of a double bond using potassium permanganate under acidic conditions. More aggressive than ozonolysis: if a carbon of the double bond carries one H, the product is a carboxylic acid (not an aldehyde). If it carries two H atoms, that carbon is fully oxidised to CO2.
Think of it as the harsh version of ozonolysis.
Carbene
A neutral, highly reactive species with a divalent carbon (two bonds and a lone pair or empty orbital). Generated in situ from CHCl3/base or from CH2I2/Zn(Cu). Adds to alkenes to form cyclopropanes by syn addition.
In simple terms, it is a carbon fragment that slams onto a double bond and makes a three-membered ring.
Simmons-Smith reaction
Cyclopropanation using CH2I2 and Zn(Cu) in ether. Generates a zinc carbenoid that adds to the alkene with syn stereochemistry.
Think of it as the cleaner, more controlled way to make a cyclopropane compared to the CHCl3/base route (which gives a dichlorocyclopropane).
Grignard reagent (RMgX)
Formed by treating an alkyl, vinyl, or aryl halide (R-X) with magnesium in ether or THF. The carbon bonded to Mg is strongly nucleophilic and basic. Reacts with water and alcohols (deprotonation) and with electrophilic carbons.
In simple terms, a Grignard is a carbon that behaves like a carbanion, ready to attack electrophiles or deprotonate acidic H atoms.
Organolithium reagent (RLi)
Formed by treating R-X with lithium metal in ether or pentane. Even more reactive than Grignard reagents. Also deprotonates water and alcohols.
Think of it as a more aggressive cousin of the Grignard.
Gilman reagent (lithium dialkylcuprate, R2CuLi)
Formed by treating 2 equivalents of RLi with CuI. The key reaction: couples with an alkyl, vinyl, or aryl halide (R'-X) to form a new C-C bond (R-R').
In simple terms, a Gilman reagent is the tool for stitching two carbon fragments together.
Alkene to epoxide: RCO3H (MCPBA is the standard choice)
Stereospecific: the oxygen adds syn, so the epoxide ring forms on the same face as the peroxyacid approaches
Cis substituents on the alkene remain cis in the epoxide; trans remain trans
Alternative route: NBS in aqueous DMSO, then aq NaOH
First forms a bromohydrin (anti addition), then base closes the ring to give the epoxide
Trans-glycol (anti-dihydroxylation): 1. MCPBA (or other peroxyacid); 2. H3O+
The epoxide forms by syn addition, then acid opens the ring with inversion, placing the two OH groups anti (trans) to each other
Products can be racemic
Cis-glycol (syn-dihydroxylation): OsO4, NMO, aqueous acetone
Both OH groups add syn, ending up cis to each other
Products can be racemic
NMO (N-methylmorpholine N-oxide) regenerates the OsO4 catalyst so only a catalytic amount is needed
Ozonolysis: 1. O3, CH2Cl2, -78 °C; 2. Zn, H3O+
Cleaves the double bond entirely, producing aldehydes and/or ketones
If a carbon of the alkene has an H on it, that H remains on the product as an aldehyde C-H
A disubstituted end gives a ketone; a monosubstituted end gives an aldehyde; a CH2= end gives formaldehyde
KMnO4 cleavage: 1. KMnO4; 2. H3O+
More oxidising than ozonolysis
An end with one H is oxidised further to a carboxylic acid (not an aldehyde)
An end with two H atoms (=CH2) is oxidised all the way to CO2
A disubstituted end still gives a ketone
Dichlorocyclopropane: 1. CHCl3; 2. KOH or t-BuOK, tBuOH
Generates dichlorocarbene (:CCl2) in situ
Stereospecific: carbene undergoes syn addition to the alkene, so the ring is cis to the existing substituents on that face
Simmons-Smith (unsubstituted cyclopropane): 1. CH2I2; 2. Zn(Cu), ether
Generates a zinc carbenoid (equivalent of :CH2)
Same syn stereochemistry as the dichlorocarbene route, but without the chlorines
Grignard reagent (RMgX):
Formation: R-X + Mg in ether or THF
R can be alkyl, vinyl, or aryl; X = Cl, Br, or I
Reaction with water or alcohols: RMgX + R'OH → R-H + R'OMgX (deprotonation, destroys the Grignard)
This means Grignard reagents are incompatible with protic solvents and with any -OH or -NH groups in the substrate
Organolithium reagent (RLi):
Formation: R-X + Li in ether or pentane
Same R groups as Grignard (alkyl, vinyl, aryl)
Same deprotonation reaction with water/alcohols: RLi + R'OH → R-H + R'OLi
More reactive (more nucleophilic, more basic) than Grignard
Gilman reagent (R2CuLi):
Formation: 2 RLi + CuI in ether → R2CuLi
Reaction: R2CuLi + R'-X → R-R' (new C-C bond)
R' can be alkyl, vinyl, or aryl; X = Cl, Br, or I
This is the main method for forming C-C bonds by coupling
Ozonolysis is used in forensic and structural chemistry to determine the position of double bonds in unknown molecules: you cleave the bond and identify the fragments. Grignard reactions are one of the most widely used methods in pharmaceutical synthesis for building complex carbon skeletons.
Students often confuse ozonolysis with KMnO4 cleavage. The critical difference: ozonolysis preserves C-H bonds as aldehydes, while KMnO4 oxidises them further to carboxylic acids (or to CO2 if two H atoms). If the exam says "identify the cleavage products" and gives you carboxylic acids, the reagent was KMnO4, not ozone.
Students forget that Grignard and organolithium reagents will immediately react with water, alcohols, or any acidic proton in the molecule. If a substrate has a free -OH or -NH, the organometallic will deprotonate it instead of doing the intended reaction. You must protect those groups first.
A common error is thinking the Gilman reagent (R2CuLi) does substitution at the carbon bearing the halide. It does, but the mechanism is not a simple SN2. The important thing for the exam is the outcome: a new C-C bond, with R replacing X.
Students mix up syn and anti dihydroxylation. OsO4 gives syn (cis) diols. The MCPBA/acid route goes through an epoxide and gives anti (trans) diols. The mnemonic: Os has an "s" for "syn."
⚠️ Ozonolysis vs KMnO4 cleavage is a near-certain exam question. Know exactly which reagent produces aldehydes vs carboxylic acids vs CO2.
⚠️ Expect a synthesis problem asking you to form a C-C bond. The two main tools: Gilman reagent coupling (R2CuLi + R'-X), and acetylide alkylation (deprotonate alkyne with NaNH2, then SN2 with a primary halide).
⚠️ Syn vs anti dihydroxylation is heavily tested. Be ready to pick the correct reagent to get a cis-diol vs a trans-diol.
⚠️ Cyclopropanation questions test whether you remember the syn addition stereochemistry: the new ring is on the same face as the carbene approached.
True or False: MCPBA adds the epoxide oxygen anti to the alkene substituents.
Answer: False. MCPBA gives syn addition.
Fill in the blank: OsO4 with NMO gives a ______ (cis/trans) glycol.
Answer: cis
True or False: Ozonolysis of a terminal alkene (R-CH=CH2) gives an aldehyde and formaldehyde.
Answer: True.
Fill in the blank: To form a new C-C bond by coupling R with R'-X, use the ______ reagent.
Answer: Gilman (R2CuLi)
Q: You treat (E)-2-pentene with OsO4 and NMO. What is the stereochemical relationship of the two OH groups in the product?
A: The two OH groups are cis (syn) to each other. OsO4 delivers both oxygens from the same face.
Q: Draw the ozonolysis products of 2-methyl-2-butene.
A: Acetone (CH3COCH3) and acetaldehyde (CH3CHO). The more substituted end gives the ketone, the monosubstituted end gives the aldehyde.
Q: What products would KMnO4/H3O+ give from the same alkene (2-methyl-2-butene)?
A: Acetone (same, it was a disubstituted end) and acetic acid (CH3COOH, because the monosubstituted end with one H is oxidised from aldehyde to carboxylic acid).
Q: Propose reagents to convert bromobenzene into biphenyl (PhPh) using organometallics.
A: 1. Treat bromobenzene with Li in ether to make PhLi. 2. React 2 eq PhLi with CuI to form Ph2CuLi (Gilman reagent). 3. React Ph2CuLi with bromobenzene to give biphenyl.
Q: You treat cyclohexene with CHCl3 and KOH. Describe the product and its stereochemistry.
A: 7,7-Dichlorobicyclo[4.1.0]heptane (a dichlorocyclopropane fused to cyclohexane). The cyclopropane ring is cis to the face from which the dichlorocarbene approached (syn addition).
Epoxidation, MCPBA, peroxyacid, meta-chloroperoxybenzoic acid, oxirane, epoxide ring, syn dihydroxylation, anti dihydroxylation, OsO4, osmium tetroxide, NMO, glycol, 1 2-diol, vicinal diol, ozonolysis, ozone cleavage, oxidative cleavage, KMnO4, potassium permanganate, carbonyl products, aldehyde vs ketone, cyclopropane, cyclopropanation, carbene, dichlorocarbene, Simmons-Smith, CH2I2 Zn Cu, Grignard reagent, RMgX, organomagnesium, organolithium, RLi, Gilman reagent, lithium dialkylcuprate, R2CuLi, C-C bond formation, coupling reaction, organic chemistry synthesis, orgo 2
Epoxide formation connects directly to epoxide ring-opening reactions (nucleophilic attack), which you will see in alcohol synthesis and in reactions with Grignard reagents. Ozonolysis and KMnO4 cleavage are the reverse perspective of carbonyl chemistry, which becomes central in later units on aldehydes and ketones. Organometallic reagents tie into the synthesis strategy section covered in the next set of notes, where you will need to plan multi-step syntheses using these C-C bond-forming tools.