Organic Chemistry, 5th ed. Marc Loudon Chapter 22 The Chemistry of Enolate Ions, Enols, and α,β Unsaturated Carbonyl Compounds Eric J. Kantorowski California Polytechnic State University San Luis Obispo, CA
Chapter 22 Overview 22.1 Acidity of Carbonyl Compounds 22.2 Enoliza9on of Carbonyl Compounds 22.3 α Halogena9on of Carbonyl Compounds 22.4 Aldol Addi9on and Aldol Condensa9on 22.5 Condensa9on Reac9ons Involving Ester Enolate Ions 22.6 Biosynthesis of FaHy Acids 22.7 Alkyla9on of Ester Enolates 22.8 Conjugate Addi9on Reac9ons 22.9 Reduc9on of α,β Unsaturated Carbonyl Compounds 22.10 Reac9ons of α,β Unsaturated Carbonyl Compounds with Organometallic Reagents 22.11 Organic Synthesis with Conjugate Addi9on Reac9ons 2
Enolates and Enols The α H of carbonyl compounds are rela9vely acidic The α C of enolates and enols can serve as a nucleophile 22.1 Acidity of Carbonyl Compounds 3
Forma6on of Enolate Anions The α H of aldehydes, ketones, esters, and even nitriles can be deprotonated 22.1 Acidity of Carbonyl Compounds 4
Forma6on of Enolate Anions An ester α H is about 10 7 9mes less acidic than aldehydes and ketones (pk a 25) The N H of primary and secondary amides is more acidic than the α H 22.1 Acidity of Carbonyl Compounds 5
Acidity and Electron Distribu6on The α C and carbonyl oxygen bear a significant amount of electron density 22.1 Acidity of Carbonyl Compounds 6
Enolate Orbital Diagram 22.1 Acidity of Carbonyl Compounds 7
Reac6ons of Enolate Ions 22.1 Acidity of Carbonyl Compounds 8
Reac6ons of Enolate Ions 22.1 Acidity of Carbonyl Compounds 9
Enols 22.2 EnolizaAon of Carbonyl Compounds 10
Enols Some enols are more stable than their corresponding carbonyl compounds 22.2 EnolizaAon of Carbonyl Compounds 11
Enols Conversion of a carbonyl compound into its enol is called enoliza6on The process is facilitated by acid or base Base catalyzed enoliza9on: 22.2 EnolizaAon of Carbonyl Compounds 12
Enols Acid catalyzed enoliza9on: 22.2 EnolizaAon of Carbonyl Compounds 13
Enols α H exchange and racemiza9on also occur under acidic condi9ons 22.2 EnolizaAon of Carbonyl Compounds 14
Acid Catalyzed α Halogena6on Enols are the reac9ve intermediates 22.3 α HalogenaAon of Carbonyl Compounds 15
Acid Catalyzed α Halogena6on In acid, only a single halogena9on occurs 22.3 α HalogenaAon of Carbonyl Compounds 16
Halogena6on of Aldehydes and Ketones In base, all α H s are subs9tuted by halogens Haloform reac6on: When acetaldehyde or a methyl ketone are used, a carboxylic acid and haloform (HCX 3 ) are produced 22.3 α HalogenaAon of Carbonyl Compounds 17
The Haloform Reac6on 22.3 α HalogenaAon of Carbonyl Compounds 18
The Haloform Reac6on 22.3 α HalogenaAon of Carbonyl Compounds 19
α Bromina6on of Carboxylic Acids This is the Hell Volhard Zelinsky (or HVZ) reac9on 22.3 α HalogenaAon of Carbonyl Compounds 20
α Bromina6on of Carboxylic Acids 22.3 α HalogenaAon of Carbonyl Compounds 21
α Bromina6on of Carboxylic Acids When a small amount of PBr 3 catalyst is used: When one full equivalent of PBr 3 is used: 22.3 α HalogenaAon of Carbonyl Compounds 22
Reac6ons of α Halo Carbonyl Compounds Most α halo carbonyl compounds are highly reac9ve in S N 2 reac9ons 22.3 α HalogenaAon of Carbonyl Compounds 23
Reac6ons of α Halo Carbonyl Compounds S N 1 reac9ons generally do not occur 22.3 α HalogenaAon of Carbonyl Compounds 24
Base Catalyzed Aldol Reac6ons The term aldol is also used generically for βhydroxyaldehydes Aldol reac6on: A reac9on of two aldehyde molecules to form a β hydroxyaldehyde 22.4 Aldol AddiAon and Aldol CondensaAon 25
Base Catalyzed Aldol Reac6ons The aldol addi9on is reversible and more favorable for aldehydes than ketones 22.4 Aldol AddiAon and Aldol CondensaAon 26
The Aldol Condensa6on With higher base concentra9on and/or higher temperatures the aldol product can dehydrate 22.4 Aldol AddiAon and Aldol CondensaAon 27
Acid Catalyzed Aldol Condensa6on With acid, aldol condensaaon products are formed; addi9on products cannot be isolated 22.4 Aldol AddiAon and Aldol CondensaAon 28
Acid Catalyzed Aldol Condensa6on 22.4 Aldol AddiAon and Aldol CondensaAon 29
Special Types of Aldol Reac6ons Claisen Schmidt condensa6on: An example of a crossed aldol reacaon Intramolecular aldol condensa9ons 22.4 Aldol AddiAon and Aldol CondensaAon 30
Synthesis with the Aldol Condensa6on Recognizing the aldol disconnec9on is synthe9cally useful 22.4 Aldol AddiAon and Aldol CondensaAon 31
Some Common Organic Group Abbrevia6ons 22.5 CondensaAon ReacAons Involving Ester Enolate Ions 32
Claisen Condensa6on A condensa9on reac9on involving esters The product is a β keto ester 22.5 CondensaAon ReacAons Involving Ester Enolate Ions 33
Claisen Condensa6on 22.5 CondensaAon ReacAons Involving Ester Enolate Ions 34
Claisen Condensa6on The reac9on is driven to comple9on by applying Le Châtelier s principle One full equivalent of the alkoxide is required At least one α H is required for success 22.5 CondensaAon ReacAons Involving Ester Enolate Ions 35
Dieckmann Condensa6on An intramolecular Claisen condensa9on 22.5 CondensaAon ReacAons Involving Ester Enolate Ions 36
Crossed Claisen Condensa6on A Claisen condensa9on of two different esters If both have α H s then a mixture of four compounds results 22.5 CondensaAon ReacAons Involving Ester Enolate Ions 37
Crossed Claisen Condensa6on The reac9on can be useful if one ester is especially reac9ve or has no α H s 22.5 CondensaAon ReacAons Involving Ester Enolate Ions 38
Synthesis with the Claisen Condensa6on 22.5 CondensaAon ReacAons Involving Ester Enolate Ions 39
Synthesis with the Claisen Condensa6on 22.5 CondensaAon ReacAons Involving Ester Enolate Ions 40
Biosynthesis of FaMy Acids The star9ng material, acetylcoenzyme A, is a thiol ester of ace9c acid 22.6 Biosynthesis of FaOy Acids 41
Biosynthesis of FaMy Acids The acetyl CoA is converted into malonyl CoA 22.6 Biosynthesis of FaOy Acids 42
Biosynthesis of FaMy Acids 22.6 Biosynthesis of FaOy Acids 43
Malonic Ester Synthesis 22.7 AlkylaAon of Ester Enolates 44
Malonic Ester Synthesis Recognizing how a target carboxylic acid can be prepared by the malonic ester synthesis is synthe9cally useful 22.7 AlkylaAon of Ester Enolates 45
Direct Alkyla6on of Enolate Ions Highly branched nitrogen bases are commonly used 22.7 AlkylaAon of Ester Enolates 46
Direct Alkyla6on of Enolate Ions 22.7 AlkylaAon of Ester Enolates 47
Acetoace6c Ester Synthesis 22.7 AlkylaAon of Ester Enolates 48
Acetoace6c Ester Synthesis 22.7 AlkylaAon of Ester Enolates 49
Acetoace6c Ester Synthesis Recognizing how a target ketone can be prepared by the acetoace9c ester synthesis is synthe9cally useful 22.7 AlkylaAon of Ester Enolates 50
Conjugate Addi6on A unique reac9vity is observed for alkenes that are conjugated with carbonyls (C=C C=O) These conjugated compounds are generally called α,β unsaturated carbonyl compounds 22.8 Conjugate AddiAon ReacAons 51
Conjugate Addi6on 22.8 Conjugate AddiAon ReacAons 52
Conjugate Addi6on With α,β unsaturated esters: With α,β unsaturated ketones: With α,β unsaturated nitriles: 22.8 Conjugate AddiAon ReacAons 53
Conjugate Addi6on vs Carbonyl Group Addi6on For ketones and aldehydes, rela9vely weak bases that give reversible carbonyl addi9on tend to give conjugate addi9on 22.8 Conjugate AddiAon ReacAons 54
Conjugate Addi6on vs Carbonyl Group Addi6on For esters conjugate addi9on competes with nucleophilic acyl subs9tu9on 22.8 Conjugate AddiAon ReacAons 55
Conjugate Addi6on of Enolate Ions Common for enolate ions derived from malonic ester deriva9ves and β keto esters Conjugate addi9ons to α,β unsaturated carbonyl compounds are called Michael addi6ons 22.8 Conjugate AddiAon ReacAons 56
The Robinson Annula6on A synthe9cally useful variant that u9lizes a Michael addi9on followed by an aldol condensa9on 22.8 Conjugate AddiAon ReacAons 57
Reduc6on of α,β Unsaturated Carbonyls Carbonyl reduc9on is not only faster, but is also irreversible (i.e., kineacally controlled) 22.9 ReducAon of α,β Unsaturated Carbonyl Compounds 58
Reduc6on of α,β Unsaturated Carbonyls The C=C of α,β unsaturated carbonyls can be selec9vely reduced by cataly9c hydrogena9on 22.9 ReducAon of α,β Unsaturated Carbonyl Compounds 59
Addi6on of Organolithium Reagents Addi9on of R Li results in carbonyl addi9on 22.10 ReacAons of α,β Unsaturated Carbonyl Compounds with Organometallics 60
Addi6on of Lithium Dialkylcuprate Reagents Addi9on of R 2 CuLi results in conjugate addi9on 22.10 ReacAons of α,β Unsaturated Carbonyl Compounds with Organometallics 61
Addi6on of Lithium Dialkylcuprate Reagents The addi9on of the nucleophilic reagent results in the forma9on of an enolate ion 22.10 ReacAons of α,β Unsaturated Carbonyl Compounds with Organometallics 62
Conjugate Addi6on in Organic Synthesis Consider any group at the β posi9on of a carbonyl (or nitrile) as a nucleophile in a conjugate addi9on reac9on 22.11 Organic Synthesis with Conjugate AddiAon ReacAons 63
Summary of C C Bond Forming Reac6ons 1. Aldol addi9on and condensa9on 2. Claisen and Dieckmann condensa9ons 3. Malonic ester synthesis 4. Alkyla9on of ester enolates 5. Acetoace9c ester synthesis 6. Conjugate addi9on of cyanide ions and enolate ions 7. Conjugate addi9on of R 2 CuLi 22.11 Organic Synthesis with Conjugate AddiAon ReacAons 64