Carbonyl Chemistry, Enolates and Aromatic Reactions, CHEM 220 – Study Notes
Difficulty: Intermediate to Advanced | Prerequisites: Nomenclature, structure/bonding, acids/bases, stereoisomerism, substitution/elimination, electrophilic addition.
Carbonyl chemistry is the largest single topic in organic chemistry. The C=O group is electrophilic at carbon and nucleophilic at oxygen, making it the most versatile functional group in the course. Nucleophilic additions (to aldehydes and ketones) and acyl substitutions (at carboxylic acid derivatives) share a common mechanistic thread, and enolate chemistry ties them together through carbon-carbon bond formation. Electrophilic and nucleophilic aromatic substitution round out the reactivity picture for aromatic systems. This document covers all of these, plus oxidation, reduction, and free radical reactions.
Nucleophiles attack the electrophilic carbonyl carbon. With aldehydes/ketones, the product stays at the tetrahedral intermediate stage (addition). With carboxylic acid derivatives, a leaving group is expelled and the carbonyl reforms (substitution). Enolates are the nucleophilic form of carbonyls and enable C-C bond formation (aldol, Claisen, Michael). EAS places electrophiles on aromatic rings; substituent directing effects control regiochemistry.
Burgi-Dunitz angle
The ~107-degree angle at which a nucleophile approaches a carbonyl carbon. Think of it as coming in slightly off-axis, not straight on.
Acyl substitution (addition-elimination)
A two-step mechanism at carboxylic acid derivatives: nucleophile adds to form a tetrahedral intermediate, then the leaving group is expelled and the carbonyl reforms.
Enolate
The conjugate base of a carbonyl compound, formed by removing an alpha-hydrogen with a strong base. Nucleophilic at both the alpha-carbon and oxygen.
Kinetic enolate
The less substituted enolate, formed with LDA at -78 degrees C (irreversible deprotonation of the less hindered alpha-H).
Thermodynamic enolate
The more substituted enolate, formed under equilibrium conditions with NaOEt or NaH.
Aldol reaction
An enolate attacks the carbonyl of another molecule, forming a beta-hydroxy carbonyl. Dehydration gives an alpha,beta-unsaturated carbonyl (aldol condensation).
Claisen condensation
Two esters react with base to give a beta-ketoester. The intramolecular version is the Dieckmann cyclisation.
Michael addition (1,4-addition)
A soft nucleophile adds to the beta-carbon of an alpha,beta-unsaturated carbonyl (conjugate addition). Followed by aldol, this gives the Robinson annulation.
Electrophilic aromatic substitution (EAS)
An electrophile replaces a hydrogen on an aromatic ring. The rate-determining step is formation of the arenium ion (Wheland intermediate).
Directing effects
Ortho/para directors (activators, plus halogens) donate electrons by resonance. Meta directors (deactivators) withdraw electrons by resonance.
The carbonyl carbon is electrophilic (delta+). Aldehydes are more reactive than ketones (less steric hindrance, less electron donation from alkyl groups).
NaBH4: mild. Reduces aldehydes and ketones to alcohols (1 degree and 2 degree respectively). Does NOT reduce esters, amides, or carboxylic acids.
LiAlH4: strong. Reduces all carbonyls, including esters (to two alcohols), amides (to amines), acid chlorides, and carboxylic acids. Use dry ether; quench carefully.
DIBAL-H at -78 degrees C: partial reduction. Esters to aldehydes (stops at hemiacetal stage). Nitriles to aldehydes.
Strong nucleophilic carbon (carbanion equivalent). These form C-C bonds.
Aldehyde + RMgX → 2 degree alcohol.
Ketone + RMgX → 3 degree alcohol.
Ester + RMgX → 3 degree alcohol (two equivalents add).
CO2 + RMgX → carboxylic acid.
Epoxide + RMgX → ring opens at less hindered C.
No acidic protons allowed in the reaction (destroy the Grignard). Solvent: dry THF or ether.
CN- attacks carbonyl C, forming an alpha-hydroxy nitrile. Useful for extending the carbon chain by one. Favoured for aldehydes; less favourable for ketones.
1 degree amine + aldehyde/ketone → imine (Schiff base) via a carbinolamine intermediate. Requires mild acid catalysis and removal of water.
2 degree amine + aldehyde/ketone → enamine (C=C-N), because there is no N-H available for elimination to C=N. Enamines are enolate equivalents.
Hemiacetal (1 ROH) → acetal (2 ROH). Requires acid catalyst and removal of water. Acetals are stable to base and nucleophiles, so they serve as protecting groups for carbonyls. Removed by aqueous acid.
Ylide (Ph3P=CR2) + aldehyde/ketone → alkene + Ph3P=O. Converts C=O to C=C. Non-stabilised ylides (alkyl) give cis (Z) alkene. Stabilised ylides (carbonyl-substituted) give trans (E) alkene. Regiospecific: the new C=C forms exactly where the C=O was.
Addition-elimination mechanism: (1) nucleophile adds to carbonyl C forming a tetrahedral intermediate, (2) leaving group is expelled and carbonyl reforms.
Acid chlorides > anhydrides > esters ~ acids > amides. The better the leaving group, the more reactive the acyl compound.
Ester hydrolysis. Acid-catalysed (Fischer): reversible, equilibrium. Base-catalysed (saponification): irreversible (carboxylate formed, not reprotonatable).
Transesterification. ROH + ester → new ester + old ROH. Acid or base catalysis. Remove alcohol product to drive forward.
Amide bond formation. Acid chloride + amine → amide (best method, fast). Anhydride + amine → amide. Carboxylic acid + amine → ammonium salt (no reaction without activation by DCC or similar coupling agent).
Reduction of esters. LiAlH4 gives two alcohols (one from the acyl portion, one from the alkoxy). NaBH4 is too mild for esters. DIBAL-H at -78 degrees C stops at the aldehyde stage.
Enol and keto forms interconvert, catalysed by acid or base. The keto form is usually dominant. Enol content increases with conjugation (phenol = 100% "enol"). Beta-dicarbonyls have significant enol content due to resonance stabilisation and intramolecular H-bonding.
Strong base (LDA, NaH, KOtBu) removes an alpha-H to form the enolate. LDA (pKa ~36, non-nucleophilic, -78 degrees C) gives the kinetic enolate (less substituted). Equilibrium bases (NaOEt, NaH) give the thermodynamic enolate (more substituted). Enolates alkylate at the alpha-carbon via SN2 with alkyl halides.
Base generates an enolate, which attacks the carbonyl C of another molecule → beta-hydroxy carbonyl (aldol product). Acid or heat drives dehydration → alpha,beta-unsaturated carbonyl (aldol condensation). Crossed aldol between two different carbonyls has regioselectivity issues unless one partner cannot form an enolate. Directed aldol: preform the enolate with LDA at -78 degrees C, then add the aldehyde.
Two esters + base (NaOEt) → beta-ketoester + alcohol. The product is deprotonated irreversibly, driving the equilibrium. Crossed Claisen works when one ester is non-enolisable (e.g. diethyl oxalate). Dieckmann cyclisation is the intramolecular Claisen.
Soft nucleophile adds to the beta-carbon of an alpha,beta-unsaturated carbonyl (conjugate addition). Hard nucleophiles add 1,2 (direct). Examples: enolate + enone, malonate ester + enone. Product: 1,4-adduct. Michael + aldol = Robinson annulation (ring formation).
Acid-catalysed: one halogenation (stops at mono); proceeds through the enol.
Base-catalysed: multiple halogenation (haloform reaction). CH3CO group + I2/NaOH → CHI3 (yellow precipitate, iodoform test) + carboxylate.
Mechanism: (1) electrophile attacks the pi system to form an arenium ion (Wheland intermediate, sp3 at attacked C), (2) proton loss restores aromaticity. The rate-determining step is formation of the arenium ion.
EAS reactions:
Halogenation: Br2/FeBr3 or Cl2/FeCl3 → ArBr or ArCl.
Nitration: HNO3/H2SO4 → ArNO2 (electrophile: NO2+).
Sulfonation: H2SO4 (fuming)/SO3 → ArSO3H. Reversible.
Friedel-Crafts alkylation: RCl/AlCl3 → ArR. Prone to rearrangement and polyalkylation.
Friedel-Crafts acylation: RCOCl/AlCl3 → ArCOR. No rearrangement; deactivates ring, stops at mono.
Directing effects:
Ortho/para directors (activators): -OH, -OR, -NH2, -NHR, -NR2, -NHCOR, alkyl. Donate electrons by resonance or induction.
Halogens: ortho/para directors but deactivators (withdraw by induction, donate by resonance).
Meta directors (deactivators): -NO2, -CN, -CHO, -COR, -COOH, -COOR, -SO3H, -CF3, -CCl3. Withdraw electrons by resonance.
Steric effects: bulky groups favour para over ortho.
Requires strong electron-withdrawing groups ortho/para to the leaving group (NO2 is best). Mechanism: addition-elimination through a Meisenheimer complex. Alternative: benzyne mechanism (elimination-addition) with strong bases on unactivated aryl halides.
Three stages: initiation (homolytic cleavage by heat or light), propagation (radical transfers), termination (radical + radical).
F2: very reactive, unselective, exothermic.
Cl2/hv: moderately selective (3 degree > 2 degree > 1 degree).
Br2/hv: very selective (3 degree >> 2 degree > 1 degree). Useful when selectivity matters.
Anti-Markovnikov HBr (peroxide-initiated): Br radical adds to the less substituted C, giving anti-Markovnikov product. Only HBr works this way.
NBS/CCl4/hv: allylic or benzylic bromination via radical substitution.
Primary alcohols → aldehyde: PCC, PDC, or Swern oxidation (stops at aldehyde).
Primary alcohols → carboxylic acid: KMnO4/H+, K2Cr2O7/H2SO4, or CrO3 (over-oxidises past aldehyde).
Secondary alcohols → ketone: PCC, PDC, Swern, or CrO3 (no over-oxidation possible).
Tertiary alcohols: resistant to oxidation (no H on C-OH).
Baeyer-Villiger: ketone + peracid → ester/lactone (O inserted adjacent to more substituted C, migration aptitude).
Tollens' test: aldehyde + Ag(NH3)2+ → silver mirror. Fehling's/Benedict's → Cu2O (brick red).
NaBH4: aldehydes/ketones → alcohols (mild).
LiAlH4: all carbonyls → alcohols; esters → two alcohols; amides → amines; acid chlorides → alcohols; nitriles → amines.
DIBAL-H at -78 degrees C: esters → aldehydes; nitriles → aldehydes.
H2/Pd or Pt: alkenes → alkanes; alkynes → cis-alkenes (Lindlar) or alkanes.
Na/NH3(l) (Birch reduction): aromatic rings → 1,4-cyclohexadienes. EWG: unsubstituted positions reduced. EDG: substituted positions remain with double bonds.
Students often think NaBH4 reduces esters. It does not. NaBH4 reduces only aldehydes and ketones. Use LiAlH4 or DIBAL for esters.
Students sometimes confuse 1,2-addition with 1,4-addition to enones. Soft nucleophiles (enolates, cuprates) add 1,4 (conjugate). Hard nucleophiles (Grignard, LiAlH4) add 1,2 (direct).
Students often assume that carboxylic acid + amine gives an amide directly. It does not: the product is an ammonium salt. You need an activating agent (DCC) or must use an acid chloride.
Students sometimes think cold KMnO4 cleaves double bonds. It does not. Cold, dilute KMnO4 gives syn-dihydroxylation (diol). Hot, concentrated KMnO4 causes cleavage.
Students often forget that secondary amines form enamines, not imines. Imines require a primary amine (need N-H for elimination to C=N).
Students confuse ortho/para directors with meta directors. Remember: electron-donating groups (EDG) direct ortho/para; electron-withdrawing groups (EWG) direct meta. Halogens are the exception: ortho/para directing but deactivating.
⚠️ NaBH4 vs. LiAlH4 selectivity is tested constantly. Know exactly which functional groups each reduces.
⚠️ Aldol, Claisen, and Michael reactions are the main C-C bond-forming tools and appear in synthesis problems.
⚠️ Directing effects in EAS are tested by asking you to predict the major product of multi-step aromatic synthesis. Order of steps matters.
⚠️ Friedel-Crafts acylation vs. alkylation: acylation avoids rearrangement and stops at mono.
⚠️ PCC vs. KMnO4 for primary alcohol oxidation: PCC stops at aldehyde, KMnO4 goes to carboxylic acid.
Fill in the blank: LiAlH4 reduces esters to ______. (two alcohols)
True or false: NaBH4 can reduce amides to amines. (False. Only LiAlH4 does that.)
Fill in the blank: In the aldol reaction, the enolate attacks the ______ of another carbonyl compound. (carbonyl carbon)
True or false: Friedel-Crafts alkylation is free from rearrangement. (False. Rearrangements and polyalkylation are common. Use acylation instead.)
Fill in the blank: Meta-directing groups are typically electron-______ groups. (withdrawing)
Q: Predict the product when butanal is treated with NaOH at room temperature.
A: Aldol reaction. The enolate of butanal attacks the carbonyl of another butanal molecule, giving 2-ethyl-3-hydroxyhexanal (the beta-hydroxy aldehyde aldol product). Heating with excess NaOH dehydrates to 2-ethylhex-2-enal.
Q: What reagent sequence converts a primary alcohol to an aldehyde without over-oxidation?
A: PCC (pyridinium chlorochromate), PDC, or Swern oxidation. All three stop at the aldehyde for primary alcohols.
Q: Predict the major product of nitration of toluene (methylbenzene) with HNO3/H2SO4.
A: The methyl group is an ortho/para director (activating). The major products are ortho-nitrotoluene and para-nitrotoluene, with para slightly favoured due to steric effects.
Q: Why does Friedel-Crafts acylation not suffer from polyalkylation?
A: The acyl group (C=O) placed on the ring is an electron-withdrawing, meta-directing deactivator. It makes the ring less reactive than the starting material, so a second substitution does not occur.
Q: Give the product of a Michael addition between diethyl malonate (with NaOEt) and methyl vinyl ketone.
A: The malonate enolate adds 1,4 to methyl vinyl ketone, giving a 1,4-adduct. After hydrolysis and decarboxylation, the product is a substituted ketone.
Carbonyl chemistry connects back to acid-base chemistry (enolate formation depends on pKa), to substitution reactions (enolate alkylation is SN2), and forward to synthesis strategy and retrosynthetic analysis. EAS connects to aromaticity (the aromatic ring must survive the reaction) and to diazonium chemistry for multi-step aromatic synthesis.
Carbonyl addition, nucleophilic addition, Burgi-Dunitz, NaBH4, LiAlH4, DIBAL-H, Grignard, organolithium, RMgX, cyanohydrin, imine, Schiff base, enamine, acetal, protecting group, Wittig reaction, ylide, acyl substitution, addition-elimination, ester hydrolysis, saponification, Fischer esterification, transesterification, amide bond, DCC, enol, enolate, tautomerism, kinetic enolate, thermodynamic enolate, LDA, aldol, aldol condensation, Claisen condensation, Dieckmann, Michael addition, conjugate addition, Robinson annulation, alpha-halogenation, haloform test, iodoform, EAS, electrophilic aromatic substitution, arenium ion, Wheland intermediate, halogenation, nitration, sulfonation, Friedel-Crafts, alkylation, acylation, ortho/para director, meta director, NAS, Meisenheimer complex, benzyne, free radical, initiation, propagation, termination, NBS, allylic bromination, oxidation, reduction, PCC, PDC, Swern, Jones, KMnO4, Baeyer-Villiger, Tollens, Birch reduction