Chapter 18 Enols and Enolates

18.1 The -Carbon Atom and its pKa 5

The reference atom is the carbonyl carbon. Terminology CH3CH2CH2CH O    The reference atom is the carbonyl carbon. Other carbons are designated , , , etc. on the basis of their position with respect to the carbonyl carbon. Hydrogens take the same Greek letter as the carbon to which they are attached. 6

Acidity of -Hydrogen O R2C CR' H Enolate ion R2C CR' O – + H+ R2C CR' •• R2C CR' • • H Enolate ion •• R2C CR' O • • – + H+ R2C CR' O •• • • – pKa = 16-20 35

Acidity of -Hydrogen (CH3)2CHCH O CCH3 O pKa = 15.5 pKa = 18.3 40

-Diketones Are Much More Acidic H3C C CH3 O H pKa = 9 H3C C CH3 O H H+ + •• – 41

-Diketones Are Much More Acidic H3C C CH3 O H – •• • • Enolate of -diketone is stabilized; negative charge is shared by both oxygens. H3C C CH3 O H •• – • • 41

-Diketones Are Much More Acidic H3C C CH3 O H – •• • • – H3C H C CH3 O •• • • H3C C CH3 O H •• – • • 41

18.2 The Aldol Condensation

A basic solution contains both the aldehyde and its enolate. Some Thoughts... RCH2CH O RCHCH O •• OH • • – •• HOH + + •• – pKa = 16-20 pKa = 15.7 A basic solution contains both the aldehyde and its enolate. Aldehydes undergo nucleophilic addition. Enolate ions are nucleophiles. What about nucleophilic addition of enolate to aldehyde? 2

RCHCH O – – RCH2CH O RCHCH RCH2CH O RCHCH H RCH2CH O 2 RCH2CH O NaOH •• • • – – RCH2CH O •• • • RCHCH •• RCH2CH O • • RCHCH H •• RCH2CH O •• • • 2 RCH2CH O NaOH RCH2CH OH CHCH R 3

Aldol Addition RCH2CH OH CHCH O R Product is called an "aldol" because it is both an aldehyde and an alcohol. 5

Aldol Addition of Acetaldehyde 2 CH3CH O CH3CH OH CH2CH O NaOH, H2O 5°C Acetaldol (50%) 6

Aldol Addition of Butanal 2 CH3CH2CH2CH O KOH, H2O 6°C (75%) CH3CH2CH2CH OH CHCH O CH2CH3 6

Aldol Condensation 2 RCH2CH O RCH2CH OH CHCH O R NaOH 3

Aldol Condensation 2 RCH2CH O RCH2CH OH CHCH O R NaOH NaOH, heat R CCH O 3

Aldol Condensation of Butanal 2 CH3CH2CH2CH O NaOH, H2O 80-100°C (86%) CH3CH2CH2CH CCH O CH2CH3 6

Dehydration of Aldol Addition Product OH H C O C O Dehydration of -hydroxy aldehyde can be catalyzed by either acids or bases. 12

Dehydration of Aldol Addition Product OH H C O OH C O • • – NaOH In base, the enolate is formed. 12

Dehydration of Aldol Addition Product OH H C O OH C O • • – NaOH The enolate loses hydroxide to form the ,-unsaturated aldehyde. 12

Aldol Reactions of Ketones 2% 98% 2 CH3CCH3 O CH3CCH2CCH3 OH CH3 The equilibrium constant for aldol addition reactions of ketones is usually unfavorable. 16

Intramolecular Aldol Condensation (96%) Na2CO3, H2O heat O OH via: 19

Intramolecular Aldol Condensation (96%) Na2CO3, H2O heat Even ketones give good yields of aldol condensation products when the reaction is intramolecular. 19

18.3 Mixed Aldol Condensations

What Is the Product? O O NaOH + CH3CH2CH CH3CH There are 4 possibilities because the reaction mixture contains the two aldehydes plus the enolate of each aldehyde. 21

What Is the Product? CH3CH O CH3CH2CH O + CH3CH OH CH2CH O CH2CH O O – • • – – CH3CHCH •• 21

What Is the Product? CH3CH O CH3CH2CH O + CH3CH2CH OH CHCH O CH3 CH2CH • • – – CH3CHCH •• 21

What Is the Product? CH3CH O CH3CH2CH O + CH3CH OH CHCH O CH3 CH2CH O • • – – CH3CHCH •• 21

What Is the Product? CH3CH O CH3CH2CH O + CH3CH2CH OH CH2CH O CH2CH O • • – – CH3CHCH •• 21

In Order to Effectively Carry Out a Mixed Aldol Condensation: Need to minimize reaction possibilities. Usually by choosing one component that cannot form an enolate. 22

Formaldehyde cannot form an enolate. HCH Formaldehyde cannot form an enolate. Formaldehyde is extremely reactive toward nucleophilic addition. 23

Formaldehyde O HCH (CH3)2CHCH2CH O (CH3)2CHCHCH O CH2OH + (52%) K2CO3 water- ether (52%) 23

Aromatic aldehydes cannot form an enolate. CH3O CH O Aromatic aldehydes cannot form an enolate. 24

Aromatic Aldehydes CH3O CH O CH3CCH3 O + NaOH, H2O 30°C CH3O CH CHCCH3 (83%) 24

Converting Ketones to Enolates for Reaction with Aldehyde Use very strong base like lithium diisopropylamide (LDA), then react with aldehyde. 24

18.4 Alkylation of Enolate Anions

Enolate Ions in SN2 Reactions Enolate ions are nucleophiles and react with alkyl halides. With a very strong base like LDA, simple enolates can be alkylated without competition from aldol condensation. Enolates derived from -diketones are more readily alkylated than simple enolates. 11

Example CH3CCH2CCH3 O O O K2CO3 + CH3I CH3CCHCCH3 CH3 (75-77%) 11

18.5 Enolization and Enol Content

Enolization (or Keto-Enol Tautomerism) H • • •• O •• CR' • • R2C H O H • • Ketone or aldehyde (keto form) R2C CR' O •• • • H Note: keto and enol forms are constitutional isomers. Enol 6

Mechanism of Enolization (Base-Catalyzed) •• O • • R2C CR' – •• O H • • • • H 6

Mechanism of Enolization (Base-Catalyzed) • • •• O •• R2C CR' – • • •• O H • • H 6

Mechanism of Enolization (Base-Catalyzed) • • O •• R2C CR' – • • •• 6

Mechanism of Enolization (Base-Catalyzed) • • – •• •• O H • • R2C CR' 6

Mechanism of Enolization (Acid-Catalyzed) • • R2C H O •• CR' • • + 6

Mechanism of Enolization (Acid-Catalyzed) + •• O H O • • • • R2C CR' H H 6

Mechanism of Enolization (Acid-Catalyzed) + •• O H O H • • R2C CR' H 6

Mechanism of Enolization (Acid-Catalyzed) •• R2C CR' H • • H O • • + 6

Percent enol is usually very small. Enol Content R2CHCR' O R2C CR' OH keto enol Percent enol is usually very small. Keto form usually 45-60 kJ/mol more stable than enol. C=O is stronger than C=C. 27

Enol Content Acetaldehyde CH3CH O H2C CH OH K = 3 x 10-7 Acetone CH3CCH3 O H2C CCH3 OH K = 6 x 10-9 27

18.11 Effects of Conjugation in -Unsaturated Aldehydes and Ketones

Relative Stability Aldehydes and ketones that contain a carbon-carbon double bond are more stable when the double bond is conjugated with the carbonyl group than when it is not. Compounds of this type are referred to as ,-unsaturated aldehydes and ketones. 2

Relative Stability CH3CH O CHCH2CCH3    (17%) K = 4.8 (83%) O CH3CH2CH CHCCH3    2

Acrolein H2C CHCH O 3

Acrolein H2C CHCH O 3

Acrolein H2C CHCH O 3

Resonance Description •• • • + – C O •• • • + – C O •• • • 7

Properties -Unsaturated aldehydes and ketones are more polar than simple aldehydes and ketones. -Unsaturated aldehydes and ketones contain two possible sites for nucleophiles to attack: Carbonyl carbon -Carbon C O •• • •  8

Greater separation of positive and negative charge Dipole Moments – – O O + + +  = 2.7 D  = 3.7 D Butanal trans-2-Butenal Greater separation of positive and negative charge 9

18.12 Conjugate Addition to -Unsaturated Carbonyl Compounds

Nucleophilic Addition to -Unsaturated Aldehydes and Ketones 1,2-Addition (direct addition): Nucleophile attacks carbon of C=O 1,4-Addition (conjugate addition): Nucleophile attacks -carbon 11

Kinetic versus Thermodynamic Control Attack is faster at C=O. Attack at -carbon gives the more stable product. 11

C O + H Y 1,2-addition Formed faster. Major product under conditions of kinetic control (i.e., when addition is not readily reversible). C O H Y 13

Enol form goes to keto form under reaction conditions. + H Y 1,4-addition C O H Y Enol form goes to keto form under reaction conditions. 13

C O + H Y 1,4-addition Keto form is isolated product of 1,4-addition. Major product under conditions of thermodynamic control. More stable than 1,2-addition product. C O H Y 13

C=O is stronger than C=C + H Y 1,2-addition 1,4-addition C=O is stronger than C=C C O H Y C O H Y 13

13

Observed with strongly basic nucleophiles: Grignard reagents LiAlH4 1,2-Addition Observed with strongly basic nucleophiles: Grignard reagents LiAlH4 NaBH4 Sodium acetylide Strongly basic nucleophiles add “irreversibly.” 17

Example O CH3CH CHCH + HC CMgBr 1. THF 2. H3O+ OH CH3CH CHCHC CH (84%) 18

Observed with weakly basic nucleophiles: Cyanide ion (CN–) 1,4-Addition Observed with weakly basic nucleophiles: Cyanide ion (CN–) Thiolate ions (RS–) Ammonia and amines (NH3, RNH2, R2NH) Azide ion (N3–) Weakly basic nucleophiles add reversibly. 17

Example via C6H5CH CC6H5 CN – O CH O C6H5CH CHCC6H5 KCN O •• – O • • CH O C6H5CH CHCC6H5 KCN ethanol, acetic acid O C6H5CHCH2CC6H5 CN (93-96%) 20

via – O CH3 SCH2C6H5 Example O CH3 O CH3 SCH2C6H5 (58%) •• • • C6H5CH2SH HO–, H2O O CH3 SCH2C6H5 (58%) 21

18.13 Addition of Carbanions to -Unsaturated Carbonyl Compounds: The Michael Reaction

Michael Addition Stabilized carbanions, such as those derived from -diketones, undergo conjugate addition to ,-unsaturated ketones. 11

Example CH3 O O H2C CHCCH3 + KOH, methanol O CH3 CH2CH2CCH3 (85%) 20

Michael Addition The Michael reaction is a useful method for forming carbon-carbon bonds. It is also useful in that the product of the reaction can undergo an intramolecular aldol condensation to form a six-membered ring. One such application is called the Robinson annulation. 11

Example: Robinson Annulation CH3 CH2CH2CCH3 OH O CH3 NaOH heat (85%) O CH3 Not isolated; dehydrates under reaction conditions. 20

18.14 Conjugate Addition of Organocopper Reagents to -Unsaturated Carbonyl Compounds

Addition of Organocopper Reagents to -Unsaturated Aldehydes and Ketones The main use of organocopper reagents is to form carbon-carbon bonds by conjugate addition to ,-unsaturated ketones. 11

O CH3 Example + LiCu(CH3)2 1. diethyl ether 2. H2O O CH3 (98%) 21