Organic Chemistry II Introduction - Home Page - VSU

1、1Spring, 2011Organic Chemistry IIAlpha Substitution ReactionsDr. Ralph C. GatroneDepartment of Chemistry and PhysicsVirginia State UniversitySpring, 20112The PositionThe carbon next to the carbonyl group is designated as being in the positionSpring, 20113ObjectivesKeto-enol tautomerismEnols substitu

2、tionEnol acidity the enolateAlkylation of the enolateCarbonyl Condensation ReactionsAldolClaisenMichael ReactionStork EnamineRobinson AnnulationSpring, 20114Enolizationconditions permit the enolization of ketonesSubstitution can occur at the alpha position through either an enol or enolate ionSpring

3、, 20115Equilibrium of TautomerismEnol formation is equilibrium processKeto form is predominant speciesEnol is present in sufficient concentration to be involved in any reactionSpring, 20116TautomersTautomers are structural isomersTautomers are not resonance formsResonance forms are representations o

4、f contributors to a single structureTautomers interconvert rapidly while ordinary isomers do notSpring, 20117EnolsThe enol tautomer is usually present to a very small extent and cannot be isolatedHowever, since it is formed rapidly, it can serve as a reaction intermediateSpring, 20118Acid Catalysis

5、of EnolizationBrnsted acids catalyze keto-enol tautomerization by protonating the carbonyl and activating the protonsSpring, 20119Base Catalysis of EnolizationBrnsted bases catalyze keto-enol tautomerizationThe hydrogens on the carbon are weakly acidic and transfer to water is slowIn the reverse dir

6、ection there is also a barrier to the addition of the proton from water to enolate carbon Spring, 201110Reactivity of EnolsEnols have very e- rich double bondsVery Nucleophilic React with variety of electrophilesSpring, 201111Generalized ReactionWhen an enol reacts with an electrophile the intermedi

7、ate cation immediately loses the OH proton to give a substituted carbonyl compoundSpring, 201112HalogenationAldehydes and ketones can be halogenated at their positions by reaction with Cl2, Br2, or I2 in acidic solutionSpring, 201113KineticsRate is independent of identity of X2Cl2, Br2, I2 react at

8、same rateRate is independent of X2Rate determining step occurs before X2Rate determining step is enolization stepRate = kketoneH+Spring, 201114Ramification of EnolizationOptically active ketones can lose optical activitySpring, 201115Elimination Reactions of-Bromoketones-Bromo ketones can be dehydro

9、brominated by base treatment to yield ,b-unsaturated ketonesSpring, 201116Alpha Bromination of Carboxylic Acids: The HellVolhardZelinskii ReactionCarboxylic acids do not react with Br2 (Unlike aldehydes and ketones)They are brominated by a mixture of Br2 and PBr3 (HellVolhardZelinskii reaction)Sprin

10、g, 201117Acidity of Alpha Hydrogen Atoms: Enolate Ion FormationCarbonyl compounds can act as weak acids (pKa of acetone = 19.3; pKa of ethane = 60)The conjugate base of a ketone or aldehyde is an enolate ion - the negative charge is delocalized onto oxygenSpring, 201118Enolate Formation - BasesKeton

11、es are weaker acids than the OH of alcohols so a a more powerful base than an alkoxide is needed to form the enolateNaOH and NaOCH3) are too weakSodium hydride (NaH), sodamide (NaNH2), or lithium diisopropylamide LiN(i-C3H7)2 are strong enough to form the enolateSpring, 201119Lithium Diisopropylamid

12、e (LDA)LDA is made from butyllithium (BuLi) and diisopropylamine (pKa 40)Soluble in organic solvents and effective at low temperature with many compounds (see Table 22.1)Not nucleophilicSpring, 201120Similar BasesLithium tetramethylpiperdideLithium dicyclohexylamideSpring, 201121Acidity of the alpha

13、 HydrogenSpring, 201122Acidity of -DicarbonylsWhen a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced Negative charge of enolate delocalizes over both carbonyl groupsSpring, 201123Acidities of Organic CompoundsSpring, 201124Reactivity of Enolate IonsThe carbon atom of an enol

14、ate ion is electron-rich and highly reactive toward electrophiles (enols are not as reactive)Spring, 201125Enolate ReactionsEnolate has two resonance formsReacts at both sites with E+ depending upon conditionsSpring, 201126Two Reactions Sites on EnolatesReaction on oxygen yields an enol derivativeRe

15、action on carbon yields an a-substituted carbonyl compoundSpring, 201127Enol Ether FormationEnolates react with trimethylsilyl chloride to form the enol etherSpring, 201128 Alkylation Alkylation occurs at CSpring, 201129Revisit Halogenation of the Enolate The Haloform ReactionBase-promoted reaction

16、occurs through an enolate ion intermediateSpring, 201130Further Reaction: CleavageMonohalogenated products are themselves rapidly turned into enolate ions and further halogenated until the trihalo compound is formed from a methyl ketoneThe product is cleaved by hydroxide with -CX3 as the leaving gro

17、up, stabilized anionSpring, 201131Halogenation: SummaryBase catalyzed processCant be stopped at one halogenCleaves methyl ketones to give HCX3Acid catalyzed processSecond halogenation is very slowUseful reaction for monohalo ketonesSpring, 201132Alpha SelenylationUsed to make unsaturated ketonesSpri

18、ng, 201133Alkylation of Enolate IonsAlkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide or tosylate and displaces the leaving groupSpring, 201134Constraints on Enolate AlkylationSN2 reaction:, the leaving group X can be chloride, bromide, iodide, or tosylat

19、eR should be primary, methyl, allylic or benzylicSecondary halides react poorly, and tertiary halides dont react at all because of competing eliminationSpring, 201135Alkylation of KetonesBase must be weaker acid than ketoneComplete proton abstractionBase cannot be nucleophilicAdds to carbonylLDA mee

20、ts both criteriaConsider:Spring, 201136Deprotonation by LDASpring, 201137AnalysisLeast hindered product predominatesSteric size of baseApproach to more substituted side restrictedIncrease in the size of the base increases the predominance of the less substituted side productSpring, 201138The Malonic

21、 Ester SynthesisFor preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atomsSpring, 201139Formation of Enolate and AlkylationMalonic ester (diethyl propanedioate) is easily converted into its enolate ion by reaction with sodium ethoxide in ethanolThe enolate i

22、s a good nucleophile that reacts rapidly with an alkyl halide to give an a-substituted malonic esterSpring, 201140DialkylationThe product has an acidic -hydrogen, allowing the alkylation process to be repeated Spring, 201141Hydrolysis and Decarboxylation The malonic ester derivative hydrolyzes in ac

23、id and loses CO2 (“decarboxylation”) to yield a substituted monoacidSpring, 201142Malonic Acid SynthesesVery useful reaction, For exampleAll can be decarboxylated to the mono acidsSpring, 201143Decarboxylation of b-KetoacidsDecarboxylation requires a carbonyl group two atoms away from the CO2HThe se

24、cond carbonyl permit delocalization of the resulting enolThe reaction can be rationalized by an internal acid-base reactionSpring, 201144DecarboxylationBeta-dicarboxylic acids readily lose CO2Other beta carboxy carbonyls should alsoLook at Ethyl acetoacetate (pKa = 11)Spring, 201145Acetoacetate Synt

25、hesisSpring, 201146Reminder of Overall ConversionThe malonic ester synthesis converts an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atomsSpring, 201147Decarboxylation of Acetoacetic Acidb-Ketoacid from hydrolysis of ester undergoes decarboxylation to yield a ketone

26、 via the enolSpring, 201148Generalization: b-Keto Esters The sequence: enolate ion formation, alkylation, hydrolysis/decarboxylation is applicable to b-keto esters in generalCyclic b-keto esters give 2-substituted cyclohexanonesSpring, 201149Carbonyl Condensation ReactionsCarbonyls behaveElectrophil

27、e or NucleophileElectrophilic BehaviorNu: add to C=ONucleophilic BehaviorEnols or enolates react with E+Condensation ReactionsCombine both reactionsUses two carbonyl compoundsOne is the Nu: through an enolateSecond is the E+Spring, 201150The Aldol ReactionEquilibrium reactionProducts favored for ald

28、ehydesReactants favored for ketonesSpring, 201151Choice of BaseLDAEnolate forms completelyNo aldol products observedNaOCH3enolate is lowAldol observedSpring, 201152Dehydration of AldolsDehydration of the aldol occurs readilyConjugated enones are formedSpring, 201153Intramolecular AldolDicarbonyl com

29、poundsReact with baseCyclic aldols resultPrepare CyclopentanonesPrepare CyclohexanonesSmaller rings cant formTS is too high in energySpring, 201154Intramolecular Aldol ReactionsSpring, 201155Claisen CondensationEsters are weakly acidicEsters undergo a reversible condensation reaction:Spring, 201156D

30、ieckmann CyclizationIntramolecular Claisen CondensationSpring, 201157Decarboxylation after Cyclizationbeta-ketoester can be alkylatedHydrolyzed and decarboxylatedSpring, 201158The Michael ReactionUnsaturated ketones react with nucleophiles1,2 reaction to yield alcohols1,4 reaction to yield substituted ketonesNucleophile used determines the result obtainedEnolates also react 1,4 with unsaturated ketonesThe Mi