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 ã 2006, Prentice Hall

Alpha Substitution Replacement of a hydrogen on the carbon adjacent to the carbonyl, C=O. => Chapter 22

Condensation with Aldehyde or Ketone Enolate ion attacks a C=O and the alkoxide is protonated. The net result is addition. => Chapter 22

Condensation with Esters Loss of alkoxide ion results in nucleophilic acyl substitution. => Chapter 22

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

Keto-Enol Tautomers (2) Tautomerism is also catalyzed by acid. In acid: => Chapter 22

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

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

Enolate Reaction As enolate ion reacts with the electrophile, the equilibrium shifts to produce more. => Chapter 22

Acid-Base Reaction to Form Enolate Very strong base is required for complete reaction. Example: => Chapter 22

 Halogenation Base-promoted halogenation of ketone. Base is consumed. Other products are water and chloride ion. => Chapter 22

Multiple Halogenations The -halo ketone produced is more reactive than ketone. Enolate ion stabilized by e--withdrawing halogen. => Chapter 22

Haloform Reaction Methyl ketones replace all three H’s with halogen. The trihalo ketone then reacts with hydroxide ion to give carboxylic acid. Iodoform, yellow ppt. => Chapter 22

Positive Iodoform for Alcohols If the iodine oxidizes the alcohol to a methyl ketone, the alcohol will give a positive iodoform test. => Chapter 22

Acid Catalyzed Halogenation of Ketones Can halogenate only one or two -H’s. Use acetic acid as solvent and catalyst. => Chapter 22

Aldehydes and Halogens Halogens are good oxidizing agents and aldehydes are easily oxidized. => Chapter 22

The HVZ Reaction The Hell-Volhard-Zelinsky reaction replaces the -H of a carboxylic acid with Br. => Chapter 22

Alkylation Enolate ion can be a nucleophile. Reacts with unhindered halide or tosylate via SN2 mechanism. => Chapter 22

Stork Reaction Milder alkylation method than using LDA. Ketone + 2 amine  enamine. Enamine is -alkylated, then hydrolyzed. => Chapter 22

Acylation via Enamines Product is a -diketone. => Chapter 22

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

Mechanism for Aldol Condensation => Also catalyzed by acid. Chapter 22

Dehydration of Aldol Creates a new C=C bond. => Chapter 22

Crossed Aldol Condensations Two different carbonyl compounds. Only one should have an alpha H. => Chapter 22

Aldol Cyclizations 1,4-diketone forms cyclopentenone. 1,5-diketone forms cyclohexenone. => Chapter 22

Planning Aldol Syntheses => Chapter 22

Claisen Condensation Two esters combine to form a -keto ester. => Chapter 22

Dieckmann Condensation A 1,6 diester  cyclic (5) -keto ester. A 1,7 diester  cyclic (6) -keto ester. => Chapter 22

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

-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. acetoacetic ester, pKa =11 => malonic ester, pKa = 13 Chapter 22

Malonic Ester Synthesis Deprotonate, then alkylate with good SN2 substrate. (May do twice.) Decarboxylation then produces a mono- or di-substituted acetic acid. => Chapter 22

Acetoacetic Acid Synthesis Product is mono- or di-substituted ketone. => Chapter 22

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

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

A Michael Reaction Enolates can react with ,-unsaturated compounds to give a 1,5-diketo product. => -keto acid Chapter 22

Robinson Annulation A Michael reaction to form a -diketone followed by an intramolecular aldol condensation to form a cyclohexenone. => Chapter 22

Mechanism for Robinson Annulation (1) => Chapter 22

Mechanism for Robinson Annulation (2) => Chapter 22

End of Chapter 22 Chapter 22