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Organic Chemistry, 6th Edition L. G. Wade, Jr. Chapter 22 Alpha Substitution and Condensations of Enols and Enolate Ions Jo Blackburn Richland College, Dallas, TX Dallas County Community College District 2006, Prentice Hall Alpha Substitution Replacement of a hydrogen on the carbon adjacent to the carbonyl, C=O. => Chapter 22 2 Condensation with Aldehyde or Ketone Enolate ion attacks a C=O and the alkoxide is protonated. The net result is addition. Chapter 22 => 3 Condensation with Esters Loss of alkoxide ion results in nucleophilic acyl substitution. => Chapter 22 4 Keto-Enol Tautomers • Tautomers are isomers which differ in the placement of a hydrogen. • One may be converted to the other. • In base: => Chapter 22 5 Keto-Enol Tautomers (2) • Tautomerism is also catalyzed by acid. • In acid: => Chapter 22 6 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. => Chapter 22 7 Acidity of -Hydrogens • pKa for -H of aldehyde or ketone ~20. • Much more acidic than alkane or alkene (pKa > 40) or alkyne (pKa = 25). • Less acidic than water (pKa = 15.7) or alcohol (pKa = 16-19). • In the presence of hydroxide or alkoxide ions, only a small amount of enolate ion is present at equilibrium. => Chapter 22 8 Enolate Reaction As enolate ion reacts with the electrophile, the equilibrium shifts to produce more. Chapter 22 => 9 Acid-Base Reaction to Form Enolate Very strong base is required for complete reaction. Example: Chapter 22 => 10 Halogenation • Base-promoted halogenation of ketone. • Base is consumed. • Other products are water and chloride ion. O O H H _ OH O _ Cl H Cl Cl H => Chapter 22 11 Multiple Halogenations • The -halo ketone produced is more reactive than ketone. • Enolate ion stabilized by e--withdrawing halogen. Cl Cl H Cl2 _ OH , H2O O O O O Cl Cl Cl Cl Cl Cl Cl Cl => Chapter 22 12 Haloform Reaction • Methyl ketones replace all three H’s with halogen. • The trihalo ketone then reacts with hydroxide ion to give carboxylic acid. O O C CH3 excess I2 C CI3 O - OH C OH - OH CI3 - O - C O HCI3 Iodoform, yellow ppt. Chapter 22 => 13 Positive Iodoform for Alcohols If the iodine oxidizes the alcohol to a methyl ketone, the alcohol will give a positive iodoform test. => Chapter 22 14 Acid Catalyzed Halogenation of Ketones • Can halogenate only one or two -H’s. • Use acetic acid as solvent and catalyst. => Chapter 22 15 Aldehydes and Halogens Halogens are good oxidizing agents and aldehydes are easily oxidized. O O C H + Br2 H2O C OH + 2 HBr => Chapter 22 16 The HVZ Reaction The Hell-Volhard-Zelinsky reaction replaces the -H of a carboxylic acid with Br. Chapter 22 => 17 Alkylation • Enolate ion can be a nucleophile. • Reacts with unhindered halide or tosylate via SN2 mechanism. O O H H - (i-Pr) 2N Li O CH3 + H CH3 Br H => Chapter 22 18 Stork Reaction • Milder alkylation method than using LDA. • Ketone + 2 amine enamine. • Enamine is -alkylated, then hydrolyzed. H O H HO+ H N N N N H H + H H H H + H + N N H CH3 Br - O Br H H CH3 + H3O Chapter 22 CH3 H + => H N+ 19 Acylation via Enamines Product is a -diketone. => Chapter 22 20 Aldol Condensation • Enolate ion adds to C=O of aldehyde or ketone. • Product is a -hydroxy aldehyde or ketone. • Aldol may lose water to form C=C. => Chapter 22 21 Mechanism for Aldol Condensation Also catalyzed by acid. => Chapter 22 22 Dehydration of Aldol Creates a new C=C bond. => Chapter 22 23 Crossed Aldol Condensations • Two different carbonyl compounds. • Only one should have an alpha H. => Chapter 22 24 Aldol Cyclizations • 1,4-diketone forms cyclopentenone. • 1,5-diketone forms cyclohexenone. => Chapter 22 25 Planning Aldol Syntheses => Chapter 22 26 Claisen Condensation Two esters combine to form a -keto ester. O O CH3 O C CH2 R pKa = 24 R CH3 O CH3 base CH3 O C CH R enolate ion O O R CH2 C O CH3 O O CH3 O C CH R O C CH R O _ O O C C CH3 C CH2R R Chapter 22 CH2 C O CH3 O C CH R pKa = 11 O C CH2R _ => OCH3 27 Dieckmann Condensation • A 1,6 diester cyclic (5) -keto ester. • A 1,7 diester cyclic (6) -keto ester. => Chapter 22 28 Crossed Claisen • Two different esters can be used, but one ester should have no hydrogens. • Useful esters are benzoates, formates, carbonates, and oxalates. • Ketones (pKa = 20) may also react with an ester to form a -diketone. => Chapter 22 29 -Dicarbonyl Compounds • 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. O O O CH3CH2O C CH2 C OCH2CH3 malonic ester, pKa = 13 CH3 O C CH2 C OCH2CH3 acetoacetic ester, pKa =11 => Chapter 22 30 Malonic Ester Synthesis • Deprotonate, then alkylate with good SN2 substrate. (May do twice.) • Decarboxylation then produces a monoor di-substituted acetic acid. => Chapter 22 31 Acetoacetic Acid Synthesis Product is mono- or di-substituted ketone. => Chapter 22 32 Conjugate Additions • When C=C is conjugated with C=O, 1,2-addition or 1,4-addition may occur. • A 1,4-addition of an enolate ion is called the Michael reaction. => Chapter 22 33 Michael Reagents • Michael donors: enolate ions stabilized by two electron-withdrawing groups. -diketone, -keto ester, enamine, -keto nitrile, -nitro ketone. • Michael acceptors: C=C conjugated with carbonyl, cyano, or nitro group. conjugated aldehyde, ketone, ester, amide, nitrile, or a nitroethylene. => Chapter 22 34 A Michael Reaction Enolates can react with ,-unsaturated compounds to give a 1,5-diketo product. COOC2H5 COOC2H5 H O O _ CH3CH2O C CH H C H O C C CH3 CH3CH2O C CH CH2 _ H O C C CH3 H OC2H5 COOC2H5 COOH O HO C CH CH2 O HO C CH2 CH2 H O C C CH3 H + H3O heat O CH3CH2O C CH CH2 H O C C CH3 H H O C C CH3 => H -keto acid Chapter 22 35 Robinson Annulation A Michael reaction to form a -diketone followed by an intramolecular aldol condensation to form a cyclohexenone. H CH3 H O H C + H3C CH3 _ C H C O OH O => Chapter 22 36 Mechanism for Robinson Annulation (1) => Chapter 22 37 Mechanism for Robinson Annulation (2) => Chapter 22 38 End of Chapter 22 Chapter 22 39