Bài giảng Organic Chemistry - Chapter 18: Enols, Enolates, Enals, and Enones

Chapter 18: Enols, Enolates, Enals, and Enonesα-Hydrogens in carbonyl compounds are acidicDeprotonation of a carbonyl compound:Stoichiometric deprotonation: KH, LDACompare: propene ~40 Dominant formEnolates: “Oxaallyls”Acetone enolateNote: RLi and RMgX usually add to carbonylEquilibrium deprotonation: NaOH, NaORReactivity: Ambident, attack on either O or C:Alkylation on C is dominantKinetic protonation on O, followed by tautomerismTautomerizationEnolate formation can be regioselectiveTraces of acid (free amine, slight excess of ketone) give equilibration to more stable enolateKeto-Enol EquilibriaH+ or –OH cat.K <<1 usuallyWe often don’t need stoichiometric enolate formation: Acid or base forms enols or enolates in equilibrium concentrations, sufficient for many further transformations.H+ or –OH cat.Worse, because CH3 stabilizes keto form“Keto form”“Enol form”Mechanisms of enol to keto tautomerization (and the reverse):Acid-catalyzedBase-catalyzedHow is enolization detected ? Most easily by NMR: H-D exchange with D2O, D+, or D2O, -OD (α-H signals disappear).Other consequence of enolization: Loss of stereochemistryCisMore stableTransHalogenation: uses catalytic H+ or HO-Acid-catalyzed:Base-catalyzed:+ Cl2HCl+ HCl+ Cl2NaOH+NaClStops here!Perchlorination Mechanisms: Acid-catalyzedEthenol is e-richLike a Markovnikov alkene bromination, but open cation, not:Br substituent slows further halogenationBromonium ionBoth are octetsLess basicOctetOctet, but strainedBase-catalyzedBr substituent increases the acidity of the α-Hs: Speeds further halogenation.Like an SN2 reactionAlkylationAlkylation of enolates can be difficult to control1. Enolate ion is a strong base: E2 problems • Alkylation best when using halomethanes, primary haloalkanes, or allylic halides2. Aldehydes are attacked by enolates at carbonyl carbon “Aldol condensation” (later) • Better to use the less reactive (at carbonyl) ketones Ketones have their own problems • Unsymmetrical ketones lead to two regioisomeric products • Product may lose another α–hydrogen and be alkylated further Solution to these Problems: EnaminesAn alternative route for the alkylation of aldehydes and ketones.Enamines are neutral (no E2 of haloalkane) and their carbon–carbon double bond is electron-rich. The β-carbon is nucleophilic by resonance, can be alkylated. Examples:Procedure:1. Enamine formation using an auxiliary amine, e.g. 2. Alkylation3. Acidic aqueous work-up (hydrolysis)Aldol CondensationStereochemistry depends on stericsCatalytic(Aldehyde alcohol)50-60% Isolable, if wantedOne pot:Can also be done stoichiometrically with preformed enolate:Mechanism of Aldol Formation:Aldol Dehydration: Stepwise through enolateAldolThe “crossed” aldol reaction is nonselective......unless a nonenolizable aldehyde is present:Ketones may undergo aldol condensation:EndothermicEquilibrium driven forward by dehydration:ExothermicIntramolecular AldolXStrainThermodynamically and kinetically favoredStrained bridgeXXFour-membered rings and top one cannot dehydrate-OH, Δ-H2OSix-membered ring90%GoodOXα,β-Unsaturated Aldehydes and KetonesAcidicBasicAlso acidic pKa ~ 16-20OHHHHHHHHα-Halogenation–Elimination Oxidation of Allylic Alcohols with MnO2RCH=CHCH2OHMnO2 or PCCPreparation3. Aldol Condensation4. Wittig Reaction – Stabilized YlidesStabilized by extra resonance: Can be isolated, reacts only with aldehydes, not ketones81%Selective for transMakes formyl unreactivefor the Wittig reactionStabilized by resonanceProperties of α,β-Unsaturated Carbonyls Consequence: β,γ-Unsaturated systems rearrange to the α,β-enone isomersAcid- or base-catalyzedMechanism:Acid-catalyzedReprotonation to the more stable cationBase-catalyzedReactivity of α,β-Unsaturated Carbonyls -Undergo many reactions characteristic of alkenes and ketones/aldehydesExamples: H2, Pd/CCH3LiNote:RLi and RMgXdo not deprotonate but prefer to add toaldehydes and ketonesIn addition, new reactivity for whole system (as in conjugated dienes): 1,4-Addition (conjugate addition)1. Hydrogen Cyanide Conjugate AdditionNot cyanohydrin formation: 1,2-Addition reversible; 1,4-addition product more stableMechanism:2. O and N Nucleophiles a. H2O (or ROH): Conjugate Hydration (or Ether Formation)Mechanism (same for RO–):b. Amine Additions, RNHR’: β-AminationIntramolecularH+ or -OHProduct mainly cis due to ring fusion3. Organometallics (not reversible)RLi reagents attack mainly at C=O (1,2-)But: Cuprates, R2CuLi, add to β-carbon (1,4-) Example of 1,4-addition with cuprate:Note: Cuprates are organometallics and moisture sensitive. The reaction is in aprotic media, therefore it generates an enolate ion as the product. Protonation occurs on work-up.The initial enolate product of cuprate 1,4-addition can be trapped with RX: Double alkylation of the C=C double bond!Mostly trans due to sterics(C6H5)2CuLi2. CH3I84% Enolate Ions As Nucleophiles Enolates attack α,β-unsaturated ketones and aldehydes in a 1,4-sense: Michael Addition (conjugate aldol addition). Works with simple aldehydes and ketones.Mechanism:Forms the thermodynamic enolateArthur Michael1853-1942 “Donor” “Acceptor”1,5-Dicarbonyl compoundRobinson AnnulationCombines the Michael Addition and intramolecular Aldol CondensationSir Robert Robinson1886-1975NP 1947Example:AnimForms the thermodynamic enolateDaubenpaper