Alpha Substitution and ondensations of Enols and Enolate Ions hap 23 W: 27, 28, 30, 31, 37, 39, 42-44, 47, 51, 54-56 Alpha Substitution Replacement of a hydrogen on the carbon adjacent to the carbonyl, =. Slide 2 1
ondensation with Aldehyde or Ketone Enolate ion attacks a = and the alkoxide is protonated. The net result is addition. Slide 3 ondensation with Esters Loss of alkoxide ion results in nucleophilic acyl substitution. Slide 4 2
Keto-Enol Tautomers Tautomers are isomers which differ in the placement of a hydrogen. ne may be converted to the other. In base: Slide 5 Keto-Enol Tautomers (2) Tautomerism is also catalyzed by acid. In acid: Slide 6 3
Equilibrium Amounts For aldehydes and ketones, the keto form is greatly favored at equilibrium. An enantiomer with an enolizable hydrogen can form a racemic mixture. Slide 7 Acidity of α-ydrogens pk a for α- of aldehyde or ketone ~20. Much more acidic than alkane or alkene (pk a > 40) or alkyne (pk a = 25). Less acidic than water (pk a = 15.7) or alcohol (pk a = 16-19). In the presence of hydroxide or alkoxide ions, only a small amount of enolate ion is present at equilibrium. Slide 8 4
Enolate Reaction As enolate ion reacts with the electrophile, the equilibrium shifts to produce more. Slide 9 Acid-Base Reaction to Form Enolate Very strong base is required for complete reaction. Example: Slide 10 5
α alogenation Base-promoted halogenation of ketone. Base is consumed. ther products are water and chloride ion. l l l Slide 11 Multiple alogenations The α-halo ketone produced is more reactive than ketone. Enolate ion stabilized by e - -withdrawing halogen. l l _ 2, 2 l l l l l l l l l Slide 12 6
aloform Reaction Methyl ketones replace all three s with halogen. The trihalo ketone then reacts with hydroxide ion to give carboxylic acid. 3 excess I 2 - I 3 - - I 3 - I 3 Iodoform, yellow ppt. Slide 13 Positive Iodoform for Alcohols If the iodine oxidizes the alcohol to a methyl ketone, the alcohol will give a positive iodoform test. Slide 14 7
Acid atalyzed alogenation of Ketones an halogenate only one or two α- s. Use acetic acid as solvent and catalyst. Slide 15 Aldehydes and alogens alogens are good oxidizing agents and aldehydes are easily oxidized. + Br 2 2 + 2 Br Slide 16 8
The VZ Reaction The ell-volhard-zelinsky reaction replaces the α - of a carboxylic acid with Br. Slide 17 Alkylation Enolate ion can be a nucleophile. Reacts with unhindered halide or tosylate via S N 2 mechanism. (i-pr) 2 N - Li + 3 Br 3 Slide 18 9
Stork Reaction Milder alkylation method than using LDA. Ketone + 2 amine enamine. Enamine is α-alkylated, then hydrolyzed. N + + N N + N N 3 Br + N Br - 3 + 3 3 + N + Slide 19 Acylation via Enamines Product is a β-diketone. Slide 20 10
Aldol ondensation Enolate ion adds to = of aldehyde or ketone. Product is a β-hydroxy aldehyde or ketone. Aldol may lose water to form =. Slide 21 Mechanism for Aldol ondensation Also catalyzed by acid. Slide 22 11
Dehydration of Aldol reates a new = bond. Slide 23 rossed Aldol ondensations Two different carbonyl compounds. nly one should have an alpha. Slide 24 12
Aldol yclizations 1,4-diketone forms cyclopentenone. 1,5-diketone forms cyclohexenone. Slide 25 Planning Aldol Syntheses Slide 26 13
laisen ondensation Two esters combine to form a β-keto ester. 3 2 R base 3 R pka = 24 enolate ion R 2 3 R 2 3 R 3 R 3 3 R _ 2 R 3 R pka = 11 2 R _ 3 Slide 27 Dieckmann ondensation A 1,6 diester cyclic (5) β-keto ester. A 1,7 diester cyclic (6) β-keto ester. Slide 28 14
rossed laisen Two different esters can be used, but one ester should have no α hydrogens. Useful esters are benzoates, formates, carbonates, and oxalates. Ketones (pk a = 20) may also react with an ester to form a β-diketone. Slide 29 β-dicarbonyl ompounds More acidic than alcohols. Easily deprotonated by alkoxide ions and alkylated or acylated. At the end of the synthesis, hydrolysis removes one of the carboxyl groups. 3 2 2 2 3 3 2 2 3 malonic ester, pk a = 13 acetoacetic ester, pk a =11 Slide 30 15
Malonic Ester Synthesis Deprotonate, then alkylate with good S N 2 substrate. (May do twice.) Decarboxylation then produces a mono- or di-substituted acetic acid. Slide 31 Acetoacetic Acid Synthesis Product is mono- or di-substituted ketone. Slide 32 16
onjugate Additions When = is conjugated with =, 1,2-addition or 1,4-addition may occur. A 1,4-addition of an enolate ion is called the Michael reaction. Slide 33 Michael Reagents Michael donors: enolate ions stabilized by two electron-withdrawing groups. β-diketone, β-keto ester, enamine, β-keto nitrile, α-nitro ketone. Michael acceptors: = conjugated with carbonyl, cyano, or nitro group. conjugated aldehyde, ketone, ester, amide, nitrile, or a nitroethylene. Slide 34 17
A Michael Reaction Enolates can react with α,β-unsaturated compounds to give a 1,5-diketo product. 3 2 2 5 _ 3 3 2 2 5 2 _ 3 2 5 2 3 3 + heat 3 2 2 5 2 3 3 2 2 δ-keto acid Slide 35 Robinson Annulation A Michael reaction to form a 1,5-diketone followed by an intramolecular aldol condensation to form a cyclohexenone. 3 + 3 _ 3 Slide 36 18
Mechanism for Robinson Annulation (1) Slide 37 Mechanism for Robinson Annulation (2) Slide 38 19
End of hapter 23 Slide 39 20