Báo cáo Enolates Enamines

Chapter 19 Enolates and Enamines 19-1 Formation of an Enolate Anion ◆ Enolate anions are formed by treating an aldehyde, ketone, or ester, which has at least one α-hydrogen, with base, O CH3 -C-H + NaOH O Na+ O H C C-H +H2 O H C C-H H H An enolate anion • Most of the negative charge in an enolate anion is on oxygen oxygen Reactive carbon 19-2 Enolate Anions ◆ Enolate anions are nucleophiles in SN2 reactions and carbonyl addition reactions, O SN2 R – R + R' Br nucleophilic substitution R An enolate A 1° haloalkane anion or sulfonate Carbonyl addition O R – R An enolate anion R' A ketone R' + Br R R R nucleophilic    addition O R + R' SN O O O R R R R' R' A tetrahedral carbonyl  addition intermediate 19-3 The Aldol Reaction ◆ The most important reaction of enolate anions is nucleophilic addition to the carbonyl group of another molecule of the same or different compound • Catalysis: Base catalysis is most common although acid also works Enolate anions only exist in base 19-4 The Aldol Reaction ◆ The product of an aldol reaction is: • a β-hydroxyaldehyde acid OH O O H O α NaOH β + CH3 -C-H CH2 -C-H CH3 -CH-CH2 -C-H Acetaldehyde Acetaldehyde 3­Hydroxybutanal (a β­hydroxyaldehyde;  racemic) • or a β-hydroxyketone O H O CH3-C-CH3 + CH2-C-CH3 Acetone Acetone acid OH O α β CH3-C-CH2-C-CH3 CH3 4­Hydroxy­4­methyl­2­pentanone (a β­hydroxyketone) Ba(OH)2 19-5 Mechanism: the Aldol Reaction, Base ◆ Base-catalyzed aldol reaction (good nucleophile) Step 1: Formation of a resonance-stabilized enolate anion H-O O + H-CH2 -C-H pKa  20 (weaker acid) H-O-H + pKa 15.7 (stronger acid) O CH2 -C-H O CH2 =C-H An enolate anion Step 2: Carbonyl addition gives a TCAI O CH3-C-H + O CH2-C-H O OCH3-CH-CH2-C-H A tetrahedal carbonyl addition intermediate Step 3: Proton transfer to O- completes the aldol reaction 19-6 Mechanism: the Aldol Reaction: Acid catalysis ◆ Before showing the mechanism think about what is needed • On one molecule the beta carbon must have nucleophilic capabilities to supply an electron pair • On the second molecule the carbonyl group must function as an electrophile • One or the other molecules must be sufficiently reactive 19-7 Mechanism: the Aldol Reaction: Acid catalysis ◆ Acid-catalyzed aldol reaction (good electrophile) • Step 1: Acid-catalyzed equilibration of keto and enol forms O OH Nucleophilic CH3 -C-H HA CH2 =C-H carbon • Step 2: Proton transfer from HA to the H carbonyl group of a second molecule of O O aldehyde or ketone CH -C-H + CH -C-H + H A A Reactive carbonyl 19-8 Mechanism: the Aldol Reaction: Acid catalysis • Step 3: Attack of the enol of one molecule on the protonated carbonyl group of the other molecule H Proton H • Step 4: transfer to A- completes the OH O O O reaction CH -C-H + CH =C-H + :ACH -CH-CH -C-H + H-A 3 (racemic) This may look a bit strange but compare to 19-9 The Aldol Products: Dehydration to alkene • Aldol products are very easily dehydrated to α,β-unsaturated aldehydes or ketones OH O CH3 CHCH2 CH warm in either acid or base O β α CH3 CH=CHCH + H2 O An α ,β­unsaturated aldehyde • Aldol reactions are reversible and often little aldol is present at equilibrium • Keq for dehydration is generally large • If reaction conditions bring about dehydration, good yields of product can be obtained 19-10 Michael Reaction, Cautions 1,4 vs 1,2 • Resonance-stabilized enolate anions and enamines are weak bases, react slowly with α,β-unsaturated carbonyl compounds, and give 1,4-addition products • Organolithium and Grignard reagents, on the other hand, are strong bases, add rapidly to carbonyl groups, and given primarily 1,2addition O PhLi Phenyl­ lithium + 4­Methyl­3­ penten­2­one - + Ph O Li Ph OH H2 O HCl 4­Methyl­2­phenyl­ 3­penten­2­ol 19-45 Michael Reaction: Thermodynamic vs Kinetic O C C C fast - ROH - + RO C C C Nu 1,2­Addition (less stable product) Nu O Nu: + C C C slow OH - O Nu C C C ROH H O Nu C C C + RO- 1,4­Addition (more stable product) Addition of the nucleophile is irrevesible for strongly basic carbon nucleophiles (kinetic product) 19-46 Micheal-Aldol Combination Carbanion site O α, β unsaturated O NaOEt, Et OH + (Michael reaction) COOEt Ethyl 2­oxocyclohex­ 3­Buten­2­one    anecarboxylate (Methyl vinyl ketone) O COOEt O O NaOEt, Et OH (Aldol reaction) COOEt Dieckman 19-47 Retrosynthesis of 2,6-Heptadione these three  carbons from acetoacetic ester O O this bond formed in a Michael reaction O O O O + this carbon lost by  decarboxylation COOH COOEt       Ethyl  acetoacetate Methyl vinyl     ketone Recognize as substituted acetone, aae synthesis Recognize as Nucleophile – C – C – CO Michael 19-48 Michael Reactions • Enamines also participate in Michael reactions N CH2=CHCN O CN H2O, HCl Pyrrolidine enamine of cyclohexanone + + N Cl H H (racemic) 19-49 Gilman Reagents vs other organometallics ◆ Gilman reagents undergo conjugate addition to α,βunsaturated aldehydes and ketones in a reaction closely related to the Michael reaction O O (CH3 )2 CuLi, ether, ­78°C CH3 • H2 O, HCl 3­Methyl­2­ cyclohexenone Gilman reagents CH3 CH3 3,3­Dimethyl­ cyclohexanone among are unique organometallic compounds in that they give almost exclusively 1,4-addition • Other organometallic compounds, including Grignard reagents, add to the carbonyl carbon by 1,2-addition 19-50 Crossed Enolate Reactions using LDA ◆ ◆ ◆ With a strong enough base, enolate anion formation can be driven to completion The base most commonly used for this purpose is lithium diisopropylamide , LDA LDA is prepared by dissolving diisopropylamine in THF and treating the solution with butyl lithium [( CH3 ) CH] NH + CH3 (CH2 ) 3Li Diisopropylamine Butyllithium (pK a 40 (stronger base) (stronger acid) [( CH3 ) CH] N-Li+ + CH3 (CH2 ) 2CH3 Lithium diisopropylamde (weaker base) Butane pK a 50 (weaker acid) LDA 19-51 Crossed Enolate Reactions using LDA ◆ The crossed aldol reaction between acetone and an aldehyde can be carried out successfully by adding acetone to one equivalent of LDA to completely preform its enolate anion, which is then treated with the aldehyde O Acetone LDA ­78°C O O Li 1.C6H5CH2CH - OH O + Lithium enolate C6H5 2. H2O 4­Hydroxy­5­phenyl­2­pentanone (racemic) 19-52 Examples using LDA Crossed aldol Michael Alkylation Acylation 19-53 Crossed Enolate Reactions using LDA Question: For ketones with nonequivalent α-hydrogens, can we selectively utilize the nonequivalent sites? Answer: A high degree of regioselectivity exists and it depends on experimental conditions 19-54 Crossed Enolate Reactions using LDA • When 2-methylcyclohexanone is treated with a slight excess of LDA, the enolate is almost slight excess  entirely the less substituted enolate anion of base O-Li+ O-Li+ O + LDA 0°C + [( CH3 ) CH] NH + (racemic)  99% 1% • When 2-methylcyclohexanone is treated with LDA where the ketone is in slight excess, the productslight excess  is richer in the more substituted of the ketone O O-Li+ O-Li+ enolate + LDA 0°C + [( CH3 ) CH] NH + (racemic)  10% 90% 19-55 Crossed Enolate Reactions using LDA ◆ ◆ The most important factor determining the composition of the enolate anion mixture is whether the reaction is under kinetic (rate) or thermodynamic (equilibrium) control Thermodynamic Control: Experimental conditions that permit establishment of equilibrium between two or more products of a reaction.The composition of the mixture is determined by the relative stabilities of the products 19-56 Crossed Enolate Reactions using LDA • Equilibrium among enolate anions is established when the ketone is in slight excess, a condition under which it is possible for proton-transfer reactions to occur between an enolate and an α-hydrogen of an unreacted ketone Thus, equilibrium is established + O O Li O-Li+ O between H alternative enolate anions CH3 + (racemic) + Less stable enolate anion (racemic) More stable enolate anion (racemic) 19-57 Crossed Enolate Reactions using LDA ◆ Kinetic control: Experimental conditions under which the composition of the product mixture is determined by the relative rates of formation of each product First formed dominates • In the case of enolate anion formation, kinetic control refers to the relative rate of removal of alternative α-hydrogens • With the use of a bulky base, the less hindered hydrogen is removed more rapidly, and the major product is the less substituted enolate anion • No equilibrium among alternative structures is set up 19-58 Example 1.01 mol LDA, kinetic control 0.99 mol LDA, thermodynamic control 19-59 ... 19-28 Formation of Enamines ◆ Again, enamines are formed by the reaction of a 2° amine with the carbonyl group of an aldehyde or ketone • The 2° amines most commonly used to prepare enamines are pyrrolidine... Formation of Enamines • Examples: O + + + H N N H OH H -H2 O An enamine O O O + N H N + H O + H N OH -H2 O N An enamine 19-30 Enamines – Alkylation at α position ◆ The value of enamines is that... bond 19-27 Enamines (and imines, Schiff bases) Recall primary amines react with carbonyl compounds to give Schiff bases (imines), RN=CR2 Primary amine But secondary amines react to give enamines