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  1. 1. Chapter 18: Enols,Chapter 18: Enols, Enolates, Enals, andEnolates, Enals, and EnonesEnones αα-Hydrogens-Hydrogens in carbonylin carbonyl compounds arecompounds are acidicacidic
  2. 2. DeprotonationDeprotonation of a carbonyl compoundof a carbonyl compound Bases for stoichiometricBases for stoichiometric deprotonation: KH, LDAdeprotonation: KH, LDA (CH(CH33))22CHCHOCHCHO ppKKaa ~ 16~ 16 CHCH33COCHCOCH33 ppKKaa ~ 20~ 20 Compare: ethene (44) or ethyne (25)Compare: ethene (44) or ethyne (25) Dominant formDominant form Enolates: “Oxaallyls” Acetone enolateAcetone enolate
  3. 3. Reactivity:Reactivity: AmbidentAmbident, attack on either O or C:, attack on either O or C: (Kinetic)(Kinetic)(Thermodynamic)(Thermodynamic) AlkylationAlkylation ProtonationProtonation Tautomerization
  4. 4. Keto-Enol EquilibriaKeto-Enol Equilibria H+ or – OH cat. KK <<1 usually<<1 usually We often don’t needWe often don’t need stoichiometricstoichiometric enolate formation: Acid orenolate formation: Acid or base forms enols or enolatesbase forms enols or enolates in equilibriumin equilibrium concentrations,concentrations, sufficient for many further transformations.sufficient for many further transformations. H+ or – OH cat. Worse, because CHWorse, because CH33 stabilizes keto formstabilizes keto form ““Keto form”Keto form” ““Enol form”Enol form”
  5. 5. Mechanisms of enol to keto tautomerizationMechanisms of enol to keto tautomerization (and the reverse):(and the reverse): Acid-catalyzedAcid-catalyzed Base-catalyzedBase-catalyzed
  6. 6. How is enolization detected ? MostHow is enolization detected ? Most easily by NMR:easily by NMR: H-D exchangeH-D exchange withwith DD22O, DO, D++ , or D, or D22O,O, -- OD (OD (αα-H signals-H signals disappear).disappear).
  7. 7. Other consequence of enolization:Other consequence of enolization: Loss of stereochemistryLoss of stereochemistry CisCis More stableMore stable TransTrans
  8. 8. HalogenationHalogenation: uses catalytic H: uses catalytic H++ or HOor HO-- Acid-catalyzed:Acid-catalyzed: Base-catalyzed:Base-catalyzed: O O Cl + Cl+ Cl22 HClHCl + HCl+ HCl O + Cl+ Cl22 O Cl Cl Cl ClNaOHNaOH +NaCl+NaCl Stops here!Stops here! PerchlorinationPerchlorination
  9. 9. MechanismsMechanisms: Acid-catalyzed: Acid-catalyzed Ethenol isEthenol is e-riche-rich Like a Markovnikov alkene bromination Br substituentBr substituent diminishesdiminishes thethe basicitybasicity ofof the oxygen:the oxygen: SlowsSlows further halogenationfurther halogenation
  10. 10. Base-catalyzedBase-catalyzed Like an SLike an SNN2 reaction2 reaction Br substituentBr substituent increasesincreases thethe acidityacidity of theof the αα-Hs:-Hs: SpeedsSpeeds further halogenation.further halogenation.
  11. 11. AlkylationAlkylation Alkylation of enolates can be difficult to controlAlkylation of enolates can be difficult to control 1. Enolate ion is a strong base: E2 problems • Alkylation best when using halomethanes, primary haloalkanes, or allylic halides 2. Aldehydes are attacked by enolates at carbonyl carbon “Aldol condensation” (later) • Better to use less reactive (at carbonyl) ketones 3. Ketones have their own problems • Product may lose another α–hydrogen and be alkylated a second time • Unsymmetrical ketones lead to two regioisomeric products LipAlknLipAlkn BBoysBBoys
  12. 12. Only oneOnly one HH Good alkylatingGood alkylating agentagent
  13. 13. Solution to theseSolution to these Problems: EnaminesProblems: Enamines An alternative route for the alkylation ofAn alternative route for the alkylation of aldehydes and ketones.aldehydes and ketones. Enamines are neutral and their carbon–carbon double bond is electron-rich. The β-carbon is nucleophilic by resonance. EthenamineEthenamine
  14. 14. Example:Example: Procedure:Procedure: 1. Enamine formation using an auxiliary amine, e.g.1. Enamine formation using an auxiliary amine, e.g. azacyclopentane;azacyclopentane; 2. Alkylation2. Alkylation 3. Acidic aqueous work-up (hydrolysis)3. Acidic aqueous work-up (hydrolysis)
  15. 15. Works also for aldehydes:Works also for aldehydes: Important, because aldehyde enolates reactImportant, because aldehyde enolates react with their precursor aldehydes in thewith their precursor aldehydes in the aldolaldol condensation.condensation.
  16. 16. Aldol CondensationAldol Condensation Can be doneCan be done stoichiometrically withstoichiometrically with preformed enolate.preformed enolate. StereochemistryStereochemistry depends on stericsdepends on sterics New bondNew bond CatalyticCatalytic (Ald(Aldehyde alcohehyde alcohol)ol)
  17. 17. Examples of a catalytic aldol condensations:Examples of a catalytic aldol condensations: 50-60% Isolable, if wanted (Sterically(Sterically controled)controled) Stepwise:Stepwise: One pot:One pot:
  18. 18. Mechanism of Aldol Formation:Mechanism of Aldol Formation: LipshLipsh MonrMonr
  19. 19. Aldol Dehydration:Aldol Dehydration: AnimnAnimn
  20. 20. The “The “crossedcrossed” aldol reaction is” aldol reaction is nonselectivenonselective......
  21. 21. ...unless a...unless a nonenolizablenonenolizable aldehyde is present:aldehyde is present: O O O H H H + NaOH, ∆ KetonesKetones may undergo aldol condensation:may undergo aldol condensation: Endothermic EquilibriumEquilibrium Exothermic
  22. 22. Intramolecular AldolIntramolecular Aldol XX XX Strain Thermodynamically and kinetically favored StrainedStrained bridgebridge O O XX XX XXFour-memberedFour-membered ring and cannotring and cannot dehydratedehydrate -- OH,OH, ΔΔ -H-H22OO Six-memberedSix-membered ringring 90%90%GoodGood O XX
  23. 23. αα,,ββ-Unsaturated-Unsaturated Aldehydes and KetonesAldehydes and Ketones AcidicAcidic BasicBasic AcidicAcidic ppKKaa ~ 16-20~ 16-20 O HH H H H HH H
  24. 24. 1.1. αα-Halogenation–Elimination-Halogenation–Elimination 2.2. Oxidation of Allylic AlcoholsOxidation of Allylic Alcohols with MnOwith MnO22 RCH=CHCHRCH=CHCH22OHOH MnOMnO22 PreparationPreparation 3. Aldol Condensation3. Aldol Condensation O R H
  25. 25. 4.4. Wittig ReactionWittig Reaction – Stabilized– Stabilized YlidesYlides Stabilized byStabilized by resonanceresonance:: Can be isolated,Can be isolated, reacts only withreacts only with aldehydesaldehydes, not, not ketonesketones ClCH2CH O P(C6H5)3 NaOH Cl- (C6H5)3PCH2CH O + (C6H5)3P CH CH O (C6H5)3P C H CH O (C6H5)3P H C CH O + : _ O H O H 81%81% TransTrans
  26. 26. Stabilized byStabilized by resonanceresonance Properties ofProperties of αα,,ββ-- Unsaturated CarbonylsUnsaturated Carbonyls
  27. 27. Consequence:Consequence: ββ,,γγ-Unsaturated systems-Unsaturated systems rearrangerearrange to theto the αα,,ββ-enone isomers-enone isomers Acid- or base-catalyzedAcid- or base-catalyzed
  28. 28. MechanismMechanism:: Acid-catalyzedAcid-catalyzed Reprotonation to the more stable cation
  29. 29. Base-catalyzedBase-catalyzed
  30. 30. Reactivity ofReactivity of αα,,ββ-- Unsaturated CarbonylsUnsaturated Carbonyls -Undergo many reactions characteristic of-Undergo many reactions characteristic of alkenes and ketones/aldehydesalkenes and ketones/aldehydes
  31. 31. ExamplesExamples:: O O HH22, Pd/C, Pd/C CHCH33LiLi O OH H
  32. 32. 1,4-Addition1,4-Addition (conjugate addition)(conjugate addition) In addition, new reactivity for wholeIn addition, new reactivity for whole system (as in conjugated dienes)system (as in conjugated dienes)
  33. 33. 1.1. Hydrogen Cyanide Conjugate AdditionHydrogen Cyanide Conjugate Addition Not cyanohydrinNot cyanohydrin formation (1,2-formation (1,2- addition reversible)addition reversible)
  34. 34. MechanismMechanism::
  35. 35. 2.2. O and N NucleophilesO and N Nucleophiles a. Ha. H22O or ROH: ConjugateO or ROH: Conjugate HydrationHydration oror Ether FormationEther Formation MechanismMechanism::
  36. 36. Ether FormationEther Formation: Strychnine: Strychnine Synthesis bySynthesis by WoodwardWoodward N N H H O H H O H BaseBase N N H H O H HO H StrychnineStrychnine
  37. 37. b. Amine Additions, RNHR’:b. Amine Additions, RNHR’: AminationAmination IntramolecularIntramolecular O HN O N -- OHOH Product mainlyProduct mainly cis due to ringcis due to ring fusionfusion
  38. 38. 3.3. OrganometallicsOrganometallics RLiRLi reagents attack mainly atreagents attack mainly at C=OC=O Cuprates,Cuprates, RR22CuLiCuLi, add, add 1,4-1,4-
  39. 39. ExampleExample of 1,4-addition with cuprate:of 1,4-addition with cuprate: Mechanism is complex, proceeds through initial electronMechanism is complex, proceeds through initial electron transfer (radical intermediates). We can, however, thinktransfer (radical intermediates). We can, however, think of it as a nucleophilicof it as a nucleophilic ββ-addition. Note: Cuprates are-addition. Note: Cuprates are organometallicsorganometallics andand moisture sensitivemoisture sensitive. The reaction is in. The reaction is in aprotic media, therefore it generates anaprotic media, therefore it generates an enolate ionenolate ion asas the product. Protonation occurs on work-up.the product. Protonation occurs on work-up.
  40. 40. The initial enolate product of cuprate 1,4-The initial enolate product of cuprate 1,4- addition can beaddition can be trappedtrapped with RX:with RX: DoubleDouble alkylationalkylation of the C=C double bond!of the C=C double bond! Mostly transMostly trans due to stericsdue to sterics O CH3 C6H5 O 1.1. (C(C66HH55))22CuLiCuLi 2.2. CHCH33II 84%84%
  41. 41. 4.4. Enolate Ions As NucleophilesEnolate Ions As Nucleophiles Enolates attackEnolates attack αα,,ββ-unsaturated ketones-unsaturated ketones and aldehydes in a 1,4-sense:and aldehydes in a 1,4-sense: Michael AdditionMichael Addition (conjugate aldol addition).(conjugate aldol addition). Works withWorks with simple aldehydes and ketones.simple aldehydes and ketones. MechanismMechanism:: 1,5-Dicarbonyl compounds Forms the thermodynamic enolate
  42. 42. Robinson AnnulationRobinson Annulation CombinesCombines thethe Michael AdditionMichael Addition andand intramolecularintramolecular Aldol CondensationAldol Condensation
  43. 43. ExampleExample:: AnimAnim More acidic: Benzylic (like allylic) Forms the thermodynamic enolate
  44. 44. Application to steroid synthesis:Application to steroid synthesis: Acidic γ-H
  45. 45. ConjugatedConjugated Aldehydes andAldehydes and VisionVision
  46. 46. Vertebrates have two kind ofVertebrates have two kind of photoreceptorphotoreceptor cells:cells: ConesCones andand RodsRods ConesCones Function in bright lightFunction in bright light Color visionColor vision RodsRods Function in dim lightFunction in dim light No colorNo color
  47. 47. • Human retina has 3 million cones andHuman retina has 3 million cones and 100 million rods100 million rods • A singleA single hhυυ of light can excite a rodof light can excite a rod cell!cell! • How?How? • Rods covered with photoreceptorsRods covered with photoreceptors • hhυυ  Atomic motionAtomic motion  NerveNerve impulseimpulse
  48. 48. Formation of rhodopsin from the protein opsin and 11-cis-retinal: The process of vision isThe process of vision is for a photon to impinge onfor a photon to impinge on rhodopsin and effectrhodopsin and effect cis-cis- trans isomerizationtrans isomerization. The. The resulting geometricalresulting geometrical change causes a nervechange causes a nerve impulse perceived as light.impulse perceived as light. Remember retinol = vitamin A, derived from carotene.Remember retinol = vitamin A, derived from carotene. Deficiency causes night blindness, then blindnessDeficiency causes night blindness, then blindness hν → cis,trans in picoseconds (10-12 sec)