Synthesis and Reactions of Enolates and Enols Enolate Alkylation 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 hydrogen and become alkylated a second time Regioisomeric Products If the starting ketone is unsymmetrical either carbon may be alkylated An example of a successful alkylation of a ketone The ketone possesses a single hydrogen and the primary allylic halide is an excellent SN2 substrate Synthesis and Reactions of Enolates and Enols Enamine Alkylation 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 carbon which makes it nucleophilic As a result of its nucleophilicity electrophiles may attack the 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 MECHANISM Alkylation of an enamine 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 Synthesis and Reactions of Enolates and Enols Aldol Condensations Attack by Enolates on the Carbonyl Function 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 unsaturated aldehyde This reaction is known as an aldol condensation It is general for aldehydes and sometimes succeeds with ketones MECHANISM 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 MECHANISM The aldol condensation yields different products depending upon the reaction temperature Low temperatures a hydroxycarbonyl compound Higher temperatures an unsaturated carbonyl compound Crossed Aldol Condensation one aldehyde not enolizable 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 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 non enolizable reactant in the presence of a base Ketones 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 Intramolecular Aldol Condesation 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 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 1 molecule rather than 2 molecules 1 molecule Reactions of Unsaturated Aldehydes and Ketones Conjugated unsaturated aldehydes and ketones are more stable than their unconjugated isomers Enones or unsaturated carbonyl groups are stabilized by resonance As a result acids or bases catalyze a rearrangement of unsaturated carbonyl compounds to their conjugated isomers MECHANISM Unsaturated aldehydes and ketones undergo the reactions typical of their component functional groups The conjugated carbonyl group of unsaturated aldehydes and ketones can undergo reactions involving the entire functional system by Acid catalyzed mechanisms Nucleophilic addition mechanisms Radical mechanisms Hydrogenation Addition of Halogen Condensations with Amine Derivatives Conjugate Additions to Unsaturated Aldehydes and Ketones The entire conjugated system takes part in 1 4 additions Addition reactions involving only one of the two bonds are called 1 2 additions Several reagents add to the conjugated system in a 1 4 manner This is called conjugate addition The nucleophilic part of the reagent attaches to the 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 H2O ROH RNH2 Conjugate Additions to Unsaturated Aldehydes and Ketones Water Alcohols Amines 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 MECHANISM Conjugate Additions to Unsaturated