Chapter 19. Carbonyl Compounds III Reaction at the α-carbon There is a basic hydrogen (α hydrogen) on α carbon, which can be removed by a strong base. 19.1 The Acidity of α-hydrogens A hydrogen bonded to a carbon is usually not acidic due to the similar electronegativities of them. A hydrogen bonded to an sp 3 hybridized carbon adjacent to a carbonyl carbon is much more acidic than hydrogens bonded to other sp 3 hybridized carbons, but less acidic than a hydrogen of water. The compounds that contain a relatively acidic hydrogen to an sp 3 hybridized carbon is called a carbon acid. Why is it acidic?: because the conjugate base which is formed after the removal of a proton is stable. Why is the base more stable? 1. The electrons left behind when a proton is removed are delocalized. 2. The electrons are delocalized onto an oxygen atom, an atom that is better able to accommodate the electrons because it is more electronegative than carbon. If the α-carbon is between two carbonyl groups, the acidity of an α-hydrogen is even greater. The ester that has a carbonyl group at the β-position is called β-keto ester. The acidity of α-hydrogens bonded to carbons flanked by two carbonyl groups increases because the electrons left behind when the proton is removed can be delocalized onto two oxygen atoms. 19.2 Keto-Enol Tautomers Keto-enol tautomers differ in the location of a double bond and a hydrogen. For most ketones, the enol tautomer is much less stable than the keto tautomer. The fraction of the enol tautomer in an aqueous solution is considerably greater for a β- diketone because the enol tautomer is stabilized by intramolecular hydrogen bonding and by conjugation of the carbon-carbon double bond with the second carbonyl group. For phenol. The enol tautomer is more stable than the keto form because the keto tautomer is not aromatic.
19.3 Keto-Enol Interconversion The interconversion of the tautomers can be catalyzed by either acids or bases. 1. In basic solution, hydroxide ion removes a proton from the α-carbon of the keto tautomer. The resulting anion has two resonance contributors; a carbanion and an enolate ion. The enolate ion contributor contributes more to the resonance hybrid because the negative charge is on oxygen atom, which is more electronegative. 2. In acidic solution, the carbonyl oxygen of the keto tautomer is protonated and water removes a proton from the α-carbon, forming the enol. 3. The steps are reversed in the base-and acid-catalyzed reactions. 19.4 How Enolate ions and Enols React An enol is a nucleophile because of the double bond. An enol is more electron rich than an alkene because the oxygen atom donates electrons by resonance, therefore an enol is a better nucleophile than an alkene. Carbonyl compounds that form enols undergo substitution reactions at the α-carbon. In acidic conditions, water removes a proton from the α-carbon of the protonated carbonyl compound. The overall reaction is an α-substitution reaction-one electrophile (E + ) is substituted for another H +. In basic solution, a base removes a proton from the α-carbon and the nucleophilic enolate ion then reacts with an electrophile. Enolate ions are much better nucleophiles than enols because they are negatively charged. Enolate ions have two electron-rich sites; the α-carbon and the oxygen. It is one of ambident nucleophiles with two nucleophilic sites on. Which nucleophilic site reacts with the electrophile depends on the elecrtophile and on the reaction conditions. Protonation occurs preferentially on oxygen because of the
greater concentration of negative charge on the more electronegative oxygen atom. However, when the electrophile is something other than a proton, carbon is more likely to be the nucleophile because carbon is a better nucleophile than oxygen. Enolate is an ambident nucleophile 19.5 Halogenation of the α-carbon of Aldehydes and Ketones In acidic solution, one α-hydrogen is substituted for a halogen. In the first step of it, the carbonyl oxygen is protonated. Water is the base that removes a proton from the α- carbon, forming an enol that reacts with an electrophilic halogen. In basic solution, all the α-hydrogens are substituted for halogens. In the first step, hydroxide ion removes a proton from the α-carbon. The enolate ion then reacts with the electrophilic halides. These two steps are repeated. Each halogenation is more rapid than the previous one because the electron-withdrawing halides increases the acidity of the remaining α-hydrogens. In acidic solution, each successive halogenation is slower than the previous one because the electron-withdrawing halides decrease the basicity of the carbonyl oxygen. In the presence of excess base and excess halogen, a methyl ketone is first converted into a trihalo-substituted ketone. The trihalomethyl is a weaker base and a better leaving group, so it replaced by the lone pair electrons on oxygen atom forming carboxylic acid. The conversion of a methyl ketone to a carboxylic acid is called a haloform reaction. 19.6 Halogenation of the α-carbon of Carboxylic Acids: The Hell-Volhard-Zelinski Reaction Carboxylic acids do not undergo substitution reactions at the α-carbon because a base will remove a proton from the OH group rather than from the α-carbon, since the OH group is more acidic. But if a carboxylic acid is treated with PBr 3 and Br 2, then the α- carbon can be brominated. It is called the Hell-Volhard-Zelinski reaction (HVZ
reaction) In the first step, PBr 3 converts the carboxylic acid into an acyl bromide. The acyl bromide is in equilibrium with its enol. Bromination of the enol forms the α- brominated acyl bromide, which is hydrolyzed to the α-brominated carboxylic acid. 19.8 Using LDA to Form an Enolate Ion The amount of carbonyl compound converted to enolate depends on the pka of the carbonyl compound and the particular base used to remove the α-hydrogen. With weak bases, only a small amount of the carbonyl compound is converted into the enolate. When lithium diisopropylamide(lda) is used, all the carbonyl compound is converted to enolate because LDA is a much stronger base than the base being formed. 19.9 Alkylation of the α-carbon of Carbonyl Compounds Alkylation of the α-carbon of a carbonyl compound is an important reaction to form a C-C bond. It is carried out by removing a proton from the α-carbon with a strong base such as LDA and then adding the appropriate alkyl halide. It is an S N 2 reaction, so it works best with methyl halides and primary alkyl halides. Ketones, esters, and nitriles can be alkylated at the α-carbon in this way. When the ketone is not symmetrical, two different products can be formed. The relative amounts of the two products depend on the reaction condition. 19.10 Alkylation and Acylation of the α-carbon using an Enamine Intermediate The electrophiles can be added to the α-carbon of an aldehyde or a ketone by converting them to an enamine, adding the electrophile, and then hydrolyzing the imine back to the ketone. The alkylation is an S N 2 reaction. Advantage to use an enamine intermediate for alkylation is that only the monoalkylated product is formed. Aldehydes and ketones can be acylated via an enamine intermediate. 19.11 Alkylation of the β-carbon: The Michael Reaction The enolate ion of α,β-diketones is a weak base, so it can react with α,β-unsaturated aldehydes or ketones. This type of reaction is called Michael reaction.
Mechanism: A base removes a proton from the α-carbon of the carbon acid, the enolate adds to the β-carbon of an α,β-unsaturated carbonyl compound, an the α-carbon obtains a proton from the solvent. If either of the reactants in a Michael reaction has an ester group, the base used to remove the α-proton is the same as the leaving group of the ester. Enamine can be used in place of enolates in Michael reaction, and we call this reaction Stork enamine reaction. 19.12 An Aldol Addition Forms β-hydroxyaldehydes or β-hydroxyketones Aldol addition: a proton is removed from an α-carbon of carbonyl compound, then the resulting anion reacts as a nucleophile and attacks the electrophilic carbonyl carbon of a second molecule of the carbonyl compound. When the reactant is an aldehyde, the addition product is a β-hydroxyaldehyde. When the reactant is a ketone, the product is a β-hydroxyketone. Since the addition reaction is reversible, good yields of the addition product are obtained only if it is removed from the solution as it is formed. In the first step, a base removes an α-proton from the carbonyl compound, forming an enolate. The enolate adds to the carbonyl carbon of a second molecule of the carbonyl compound, and the resulting negatively charged oxygen is protonated by the solvent. Ketones are less susceptible than aldehydes to attack by nucleophiles. 19.13 Dehydration of Aldol Addition Products: Formation of α,β-unsaturated Aldehydes and Ketones The β-hydroxyaldehyde and β-hydroxyketones from aldol addition are easier to be dehydrated than other alcohols because the double bond formed as the result of
dehydration is conjugated with a carbonyl group. The final product is called an enone. The overall reaction is called an aldol condensation. β-hydroxyaldehyde and β-hydroxyketones can be dehydrated under basic conditions. 19.14 The Crossed Aldol Addition If two different carbonyl compounds are used in an aldol condensation, four products can be formed because each enolate can react both with another molecule of the carbonyl compound from which the enolate was formed and with other carbonyl compound. This reaction is called a mixed aldol addition or a crossed aldol addition. The four products have similar physical properties, making them difficult to separate. If one of the carbonyl compounds does not have any α-hydrogens, only one product is formed. 19.15 A Claisen Condensation Forms a β-keto Ester Two molecules of esters undergo a condensation reaction to produce a β-keto ester. The reaction is called a Claisen condensation. One molecule of carbonyl compound is converted into an enolate by a strong base, end the enolate attacks the carbonyl carbon of a second molecule of ester. The negatively charged oxygen reforms the C=O and expels the OR group, because OR is a good leaving group. Expulsion of the alkoxide ion is reversible because the alkoxide ion can readily reform the tetrahedral intermediate by reacting with the β-keto ester. The condensation reaction can be driven to completion, if a proton is removed from the β-keto ester. Removing a proton prevents the reverse reaction from occurring, because the negatively charged alkoxide ion will not react with the negatively charged β-keto ester anion.
19.16 Other Crossed Condensations When there are two different esters, a mixture of four products will be formed. A reaction similar to a mixed Claisen condensation is the condensation of a ketone and an ester. Because the α-hydrogens of a ketone are more acidic than those of an ester, primarily one product is formed if the ketone and the base are each added slowly to the ester. 19.17 Intramolecular Condensation and Addition Reactions If a compound has two functional groups that can react with each other, an intramolecular reaction readily occurs if the product is a stable five- or six-membered ring. The addition of a base to a 1,6-diester causes the diester to undergo an intramolecular Claisen condensation forming a five-membered ring, β-keto ester. It is called a Dieckmann condensation. The mechanism of the Dieckmann condensation is the same as the mechanism of the Claisen condensation except forming a cyclic ring. 1,4 Diketone has two different sets of α-hydrogens, two different intramolecular addition products can potentially form; one with a five-membered ring, the other with a three-membered ring. The greater stability of five- and six-membered rings causes them to be formed preferentially. 1,5-Diketones and 1,7-diketones undergo intramolecular aldol additions to form sixmembered ring products. Robinson annulation: a Michael reaction + an intramolecular aldol condensation. It produces a cyclic enone products. 19.19 3-Oxocarboxylic Acids Can Be Decarboxylated The CO2 group is bonded to a carbon adjacent to a carbonyl carbon, the CO2 group can be removed, because the electrons left behind can be delocalized onto the carbonyl oxygen. 19.23 Reactions at the α-carbon in Biological Systems Biological aldol addition: dihydroxyacetone phosphate and D-glyceraldehyde-3- phosphate will produce D-fructose-1,6-diphosphate.
Biological aldol condensation: formation of cross-linked collagen from two aldehydes. Biological claisen condensation: the first step of the biosynthesis of a fatty acid, a molecule of acetyl thioester reacts with a molecule of malonyl thioestre.