18-1 Acidity of Aldehydes and Ketores:Enolate lons CHAPTER 18 eg水agg2hpdro20iotaae0roadsag8 em8lte1onscreolatsawdroen Enols,Enolates and the Aldol Condensation: a,B-Unsaturated Aldehydes and Ketones 器22e 18-2 Keto-Enol Equilibria tethetomni tuents can shift the keto-enol equilibrium agt60teoakenog。hengrg8ncroehnDeOa Hydger Evchangef i 1
1 CHAPTER 18 Enols, Enolates and the Aldol Condensation: α,β-Unsaturated Aldehydes and Ketones 18-1 Acidity of Aldehydes and Ketones: Enolate Ions The pKa values of the α-hydrogens of aldehydes and ketones range from 16 to 21, comparable to those of alcohols (15-18). Strong bases can remove α hydrogens leading to anions called enolate ions or enolates. The enolate resonance hybrid possesses partial negative charges on both carbon and oxygen and may attack electrophiles at either position. A species that can attack at two different sites to give two different products is called ambident. Alkylation of cyclohexanone enolate with 3-chloropropene occurs at the carbon atom, while protonation occurs at the oxygen atom. 18-2 Keto-Enol Equilibria An enol equilibrates with its keto form in acidic or basic solution. Keto-enol tautomerism is the interconversion of the thermodynamically more stable keto form and the enol form of a carbonyl compound. Keto-enol tautomerism proceeds by either base or acid catalysis. Either equilibration is fast and reversible in solution in the presence of the required catalyst. Substituents can shift the keto-enol equilibrium. For ordinary aldehydes and ketones, only traces of the enol form are present. The enol form is less stable by 8-12 kcal mol-1. However, for acetaldehyde, the enol form is about 100-times more stable than that of acetone because the less substituted aldehyde carbonyl is more stable than the more substituted ketone carbonyl. Enol formation leads to deuterium exchange and stereoisomerization. Treatment of a ketone with traces of acid or base in D2O solvent leads to the exchange of all the hydrogen atoms in α carbons: The number of α hydrogens in a molecule can be readily determined by following the disappearance of the 1H NMR signal as the hydrogens are sequentially replaced by deuterium
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2 Enolization also leads to the easy interconversion of stereoisomers at α-carbons. The trans isomers are sterically more stable. When an α-hydrogen is part of a stereocenter, keto-enol tautomerization can lead to racemization in the presence of a basic or acidic catalyst. 18-3 Halogenation of Aldehydes and Ketones Aldehydes and ketones react with halogens at their α-carbons. The extent of halogenation depends upon whether acidic or basic catalysis is used. The rate of halogenation is independent of the halogen concentration. The rate-determining step involves the carbonyl substrate: Further halogenation is retarded because the electronwithdrawing halogen substituent makes enolization more difficult than in the original substrate. Singly halogenated product molecules are not attacked until all of the starting aldehyde or ketone has been used up. Base catalyzed halogenation proceeds by formation of an enolate ion, which then attacks the halogen. The electron-withdrawing power of the halogen substituent makes the remaining α-hydrogens more acidic and complete halogenation of the α-carbon occurs, leaving unreacted starting material (when insufficient halogen is employed)
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3 18-4 Alkylation of Aldehydes and Ketones Alkylation of enolates can be difficult to control. The alkylation of an aldehyde or ketone enolate is an example of a nucleophilic substitution reaction. The alkylation of aldehydes and ketones is complicated by several unwanted side reactions. E2 elimination: Enolate ion is a fairly strong base. Alkylation is normally feasible using only halomethanes or primary haloalkanes. Condensation Reactions: Aldehyde alkylations usually fail because their enolate ions undergo a highly favorable condensation reaction. Multiple Alkylations: Even ketones may lose a second α-hydrogen and become alkylated a second time. Regioisomeric Products: If the starting ketone is unsymmetrical, either α-carbon may be alkylated. An example of a successful alkylation of a ketone: The ketone possesses a single α-hydrogen and the primary allylic halide is an excellent SN2 substrate. Enamines afford an alternative route for the alkylation of aldehydes and ketones. Secondary amines react with aldehydes or ketones to produce enamines. The nitrogen substituent renders the enamine carbon-carbon double bond electron-rich. This electron density is concentrated at the β-carbon, which makes it nucleophilic. As a result of its nucleophilicity, electrophiles may attack the β- carbon of the enamine. Enamines will react with haloalkanes resulting in alkylation at carbon to produce an iminium salt. The iminium salt is hydrolyzed during aqueous work-up, liberating the newly alkylated aldehyde or ketone and the original secondary amine. Alkylation of an enimine is far superior to the alkylation of an enolate. Minimizes multiple alkylations: The iminium salt formed after the first alkylation is unable to react with additional haloalkane. It can be used to prepare alkylated aldehydes (aldehyde enolates undergo aldol condensation reactions)
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4 Attack by Enolates on the Carbonyl Function: Aldol Condensation 18-5 Aldehydes undergo base-catalyzed condensations. Treating an aldehyde at low temperature with a small amount NaOH results in the formation of dimer, which, when heated, is converted into an α,β-unsaturated aldehyde. This reaction is known as an aldol condensation. It is general for aldehydes and sometimes succeeds with ketones. The hydroxide ion serves as a catalyst for the reaction. The overall reaction is not very exothermic and yields are only 50-60%. At elevated temperatures, the aldol is converted into its enolate ion, which loses hydroxide (normally a poor leaving group) to form the relatively stable final product. The aldol condensation yields different products depending upon the reaction temperature. Low temperatures: a β-hydroxycarbonyl compound Higher temperatures: an α,β-unsaturated carbonyl compound Ketones can undergo aldol condensation. The driving force of the aldol reaction of ketones is less than that of aldehydes because of the greater stability of ketones (about 3 kcal mol-1). The reaction is endothermic. The reaction can be driven towards completion by the continuous extraction of alcohol, or under more vigorous conditions, dehydration and the removal of water. 18-6 Crossed Aldol Condensation An aldol condensation between the enolate of one aldehyde and the carbonyl of another results in a crossed aldol condensation. Enolates of both aldehydes will be present and may react with the carbonyl groups of either starting compound
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5 A single aldol product can be obtained from the reaction of two different aldehydes when one of them has no enolizable hydrogen atoms. The reaction is carried out by slowly adding the enolizable aldehyde to an excess of the nonenolizable reactant in the presence of a base. 18-7 Intramolecular Aldol Condensation An intramolecular aldol condensation results from the reaction of an enolate ion and a carbonyl group within the same molecule. Reaction between different aldehyde molecules is minimized by running the reaction in a dilute solution. The kinetics of intramolecular 5-membered ring formation are also favorable. Intramolecular ring closures of ketones are a ready source of cyclic and bicyclic α,β-unsaturated ketones. Usually the least strained ring is formed (typically 5- or 6- membered). Intramolecular aldol condensations of ketones succeed while intermolecular condensations fail because of the more favorable entropy change for ring closure (1 molecule Æ 1 molecule rather than 2 molecules Æ 1 molecule). Properties of α,β-Unsaturated Aldehydes and Ketones 18-8 Conjugated unsaturated aldehydes and ketones are more stable than their unconjugated isomers. Enones, or α,β-unsaturated carbonyl groups, are stabilized by resonance. As a result, acids or bases catalyze a rearrangement of β,γ- unsaturated carbonyl compounds to their conjugated α,β-isomers. α,β-Unsaturated aldehydes and ketones undergo the reactions typical of their component functional groups. The conjugated carbonyl group of α,β-unsaturated aldehydes and ketones can undergo reactions involving the entire functional system by: Acid-catalyzed mechanisms Radical mechanisms Nucleophilic addition mechanisms
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6 Conjugate Additions to α,β-Unsaturated Aldehydes and Ketones 18-9 The entire conjugated system takes part in 1,4- additions. Addition reactions involving only one of the two π bonds are called 1,2-additions. Several reagents add to the conjugated π system in a 1,4- manner. This is called conjugate addition or 1,4-addition. The nucleophilic part of the reagent attaches to the β-carbon and the electrophilic part (proton) attaches to the carbonyl oxygen. When A is H, the initial product is an enol, which then tautomerizes to its keto form. The end result then appears to be a 1,2-addition. Oxygen and nitrogen nucleophiles undergo conjugate additions. Conjugate additions of water, alcohols, amines and similar nucleophiles undergo 1,4 additions: These reactions are generally faster and result in higher yields when a base is used as the catalyst. These processes are readily reversed at elevated temperatures. 1,4-products (carbonyl compounds) usually form rather than 1,2- products (hydrates, hemiacetals and hemiaminals) because they are more stable. Exceptions include amine derivatives for which 1,2-addition results in an insoluble product (hydroxylamine, semicarbazide or the hydrazines). Hydrogen cyanide also undergoes conjugate addition. A conjugated aldehyde or ketone may react with cyanide in the presence of acid. The reaction proceeds through a 1,4-addition pathway. •Protonation of the oxygen •Nucleophilic β attack •Enol-keto tautomerization 1,2- and 1,4-Additions of Organometallic Reagents 18-10 Organometallic reagents may attack the α,β-unsaturated carbonyl function in either 1,2- or 1,4-fashion. Organolithium reagents react almost exclusively by attacking the carbonyl carbon
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7 Grignard reagents with α,β-unsaturated aldehydes and ketones may give 1,2-addition, 1,4-addition or both, depending upon the particular substrates and conditions (Steric control). Organocuprates are much more specific, undergoing primarily 1,4-addition reactions. The first isolable intermediate in a copper-mediated 1,4-addition reaction is an enolate ion. This is trapped by the alkylating species. Conjugate Additions of Enolate Ions: Michael Addition and Robinson Annulation 18-11 Enolate ions undergo conjugate additions to α,β-unsaturated aldehydes and ketones in a reaction called the Michael addition. With some Michael acceptors, the products of the initial addition are capable of a second intramolecular aldol condensation reaction, resulting in ring formation. This sequence of Michael addition followed by intramolecular aldol condensation is called a Robinson annulation. 18 Important Concepts 1. α Hydrogens – next to a carbonyl group are acidic: • Carbonyl group is electron-withdrawing • Resulting enolate ion is resonance-stabilized 2. Electrophilic Attack – on enolates can occur at both the α carbon and the oxygen • Haloalkanes prefer the α carbon • Protonation of the oxygen leads to enols 3. Enamines – Neutral analogs of enolates • Can be β alkylated to give iminium cations which hydrolize to aldehydes and ketones during aqueous workup 4. Enol-Keto Conversion – Aldehydes and ketones are in equilibrium with their tautomeric enol forms. The equilibrium is catalyzed by acid or base. 18 Important Concepts 5. α Halogenation – of carbonyl compounds may be acid- or base-catalyzed. • Acid: attack at the double bond – subsequent renewed enolization is slowed down by the halogen • Base: attack at the carbon – subsequent renewed enolization is speeded up by the halogen 6. Aldol Condensation – Nucleophilic, reversible attack of an enolate at the carbonyl carbon of an aldehyde or ketone • Michael Addition – Attack of an enolate at the β carbon of an α,β-unsaturated carbonyl compound
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8 18 Important Concepts 7. α,β-Unsaturated Aldehydes and Ketones – • Show normal chemistry at each individual double bond • Conjugated system may react as a whole: • Acid- and base-catalyzed 1,4-additions • Cuprates add in a 1,4-manner • Alkyllithiums normally attack the carbonyl function