Chapter 222 Alpha Substitution Alpha substitution is the substitution of one of the hydrogens attached to the alpha-carbon for an electrophile. The reaction occurs through an enolate ion intermediate.
Chapter 223 Condensation with an Aldehyde or Ketone The enolate ion attacks the carbonyl group to form an alkoxide. Protonation of the alkoxide gives the addition product: a -hydroxy carbonyl compound.
Chapter 224 Condensation with Esters The enolate adds to the ester to form a tetrahedral intermediate. Elimination of the leaving group (alkoxide) gives the substitution product (a -carbonyl compound).
Chapter 225 Keto–Enol Tautomers Tautomerization is an interconversion of isomers that occur through the migration of a proton and the movement of a double bond. Tautomers are not resonance form.
Chapter 226 Base–Catalyzed Tautomerism In the presence of strong bases, ketones and aldehydes act as weak proton acids. A proton on the carbon is abstracted to form a resonance- stabilized enolate ion with the negative charge spread over a carbon atom and an oxygen atom. The equilibrium favors the keto form over the enolate ion.
Chapter 227 Acid-Catalyzed Tautomerism In acid, a proton is moved from the -carbon to oxygen by first protonating oxygen and then removing a proton from the carbon.
Chapter 228 Racemization For aldehydes and ketones, the keto form is greatly favored at equilibrium. If a chiral carbon has an enolizable hydrogen atom, a trace of acid or base allows that carbon to invert its configuration, with the enol serving as the intermediate. This is called racemization.
Chapter 229 Acidity of Hydrogens pK a for H of aldehyde or ketone ~20. Much more acidic than alkane or alkene (pK a > 40) or alkyne (pK a = 25). Less acidic than water (pK a = 15.7) or alcohol (pK a = 16–19). Only a small amount of enolate ion is present at equilibrium.
Chapter 2210 Formation and Stability of Enolate Ions The equilibrium mixture contains only a small fraction of the deprotonated, enolate form.
Chapter 2211 Energy Diagram of Enolate Reaction Even though the keto–enol tautomerism equilibrium favors the keto form, addition of an electrophile shifts the equilibrium toward the formation of more enol.
Chapter 2212 Synthesis of Lithium Diisopropylamine (LDA) LDA is made by using an alkyllithium reagent to deprotonate diisopropylamine.
Chapter 2213 Enolate of Cyclohexanone When LDA reacts with a ketone, it abstracts the -proton to form the lithium salt of the enolate.
Chapter 2214 The Halogenation of Ketones When a ketone is treated with a halogen and a base, an halogenation reaction occurs. The reaction is called base-promoted, rather than base-catalyzed, because a full equivalent of the base is consumed in the reaction.
Chapter 2215 Base-Promoted Halogenation Mechanism The base-promoted halogenation takes place by a nucleophilic attack of an enolate ion on the electrophilic halogen molecule. The products are the halogenated ketone and a halide ion.
Chapter 2216 Multiple Halogenations The -haloketone produced is more reactive than ketone because the enolate ion is stabilized by the electron-withdrawing halogen. The second halogenation occurs faster than the first. Because of the tendency for multiple halogenations this base-promoted halogenation is not widely used to prepare monohalogenated ketones. O H Cl Cl 2 OH, H 2 O _ O Cl Cl O Cl Cl Cl O Cl Cl Cl Cl
Chapter 2217 Bromoform Reaction A methyl ketone reacts with a halogen under strongly basic conditions to give a carboxylate ion and a molecule of haloform. The trihalomethyl intermediate is not isolated.
Chapter 2218 Mechanism of Haloform Formation The trihalomethyl ketone reacts with hydroxide ion to give a carboxylic acid. A fast proton exchange gives a carboxylate ion and a haloform. When Cl 2 is used, chloroform is formed; Br 2 forms bromoform ; and I 2 forms iodoform.
Chapter 2219 Positive Iodoform Test for Alcohols The iodine oxidizes the alcohol to a methyl ketone and it will give a positive iodoform test. Iodoform (CHI 3 ) is a yellow solid that will precipitate out of solution.
Chapter 2220 Propose a mechanism for the reaction of 3-pentanone with sodium hydroxide and bromine to give 2- bromo-3-pentanone. In the presence of sodium hydroxide, a small amount of 3-pentanone is present as its enolate. The enolate reacts with bromine to give the observed product. Solved Problem 1 Solution
Chapter 2221 Acid-Catalyzed α Halogenation Ketones also undergo acid-catalyzed halogenation. Acidic halogenation may replace one or more alpha hydrogens depending on how much halogen is used. Acetic acid serves as both the solvent and the acid catalyst.
Chapter 2222 Mechanism of Acid-Catalyzed α Halogenation The mechanism of acid-catalyzed halogenation involves attack of the enol form of the ketone on the electrophile halogen molecule. Loss of a proton gives the haloketone and the hydrogen halide.
Chapter 2223 Propose a mechanism for the acid-catalyzed conversion of cyclohexanone to 2-chlorocyclohexanone. Under acid catalysis, the ketone is in equilibrium with its enol form. The enol acts as a weak nucleophile, attacking chlorine to give a resonance-stabilized intermediate. Loss of a proton gives the product. Solved Problem 2 Solution
Chapter 2224 Hell–Volhard–Zelinsky (HVZ) Reaction The HVZ reaction replaces a hydrogen atom with a bromine atom on the alpha-carbon of a carboxylic acid ( -bromoacid). The acid is treated with bromine and phosphorus tribromide, followed by hydrolysis.
Chapter 2225 Hell–Volhard–Zelinski Reaction: Step 1 The enol form of the acyl bromide serves as a nucleophilic intermediate. The first step is the formation of acyl bromide, which enolizes more easily than does the acid.
Chapter 2226 Hell–Volhard–Zelinski Reaction: Step 2 The enol is nucleophilic, so it attacks bromine to give the alpha-brominated acyl bromide. In the last step of the reaction, the acyl bromide is hydrolyzed by water to the carboxylic acid.
Chapter 2227 Alkylation of Enolate Ions Because the enolate has two nucleophilic sites (the oxygen and the carbon), it can react at either of these sites. The reaction usually takes place primarily at the carbon, forming a new C—C bond.
Chapter 2228 Alkylation of Enolate Ions LDA forms the enolate. The enolate acts as the nucleophile and attacks the partially positive carbon of the alkyl halide, displacing the halide and forming a C—C bond.
Chapter 2229 Enamine Formation Ketones or aldehydes react with a secondary amine to form enamines. The enamine has a nucleophilic -carbon, which can be used to attack electrophiles.
Chapter 2230 Mechanism of Enolate Formation An enamine results from the reaction of a ketone or aldehyde with a secondary amine.
Chapter 2231 Electrostatic Potential Map of an Enamine The electrostatic potential map (EPM) of a simple enamine shows a high negative electrostatic potential (red) near the -carbon atom of the double bond. This is the nucleophilic carbon atom of the enamine.
Chapter 2232 Alkylation of an Enamine Enamines displace halides from reactive alkyl halides, giving alkylated iminium salts. The alkylated iminium salt can be hydrolyzed to the ketone under acidic conditions.
Chapter 2233 Acylation of Enamines The enamine attacks the acyl halide, forming an acyl iminium salt. Hydrolysis of the iminium salt produces the - diketone as the final product.
Chapter 2234 Aldol Condensation Under basic conditions, the aldol condensation involves the nucleophilic addition of an enolate ion to another carbonyl group. When the reaction is carried out at low temperatures, the - hydroxy carbonyl compound can be isolated. Heating will dehydrate the aldol product to the unsaturated compound.
Chapter 2235 Base-Catalyzed Aldol Condensation: Step 1 During Step 1, the base removes the - proton, forming the enolate ion. The enolate ion has a nucleophilic -carbon.
Chapter 2236 Base-Catalyzed Aldol Condensation: Step 2 The enolate attacks the carbonyl carbon of a second molecule of carbonyl compound.
Chapter 2237 Base-Catalyzed Aldol Condensation: Step 3 Protonation of the alkoxide gives the aldol product.
Chapter 2238 Dehydration of Aldol Products Heating a basic or acidic aldol dehydration of the alcohol functional group. The product is a , -unsaturated conjugated aldehyde or ketone. An Aldol condensation, followed by dehydration, forms a new carbon–carbon double bond.
Chapter 2241 Propose a mechanism for the base-catalyzed aldol condensation of acetone (Figure 22-2). The first step is formation of the enolate to serve as a nucleophile. The second step is a nucleophilic attack by the enolate on another molecule of acetone. Protonation gives the aldol product. Solved Problem 3 Solution
Chapter 2242 Aldol Cyclization Intramolecular aldol reactions of diketones are often used for making five- and six-membered rings. Rings smaller or larger than five or six members are not favored due to ring strain or entropy.
Chapter 2243 Retrosynthesis of Aldol Condensation
Chapter 2244 Claisen Condensation The Claisen condensation results when an ester molecule undergoes nucleophilic acyl substitution by an enolate.
Chapter 2246 Crossed Claisen Two different esters can be used, but one ester should have no hydrogens. Useful esters are benzoates, formates, carbonates, and oxalates. Ketones (pK a = 20) may also react with an ester to form a -diketone.
Chapter 2247 Crossed Claisen Condensation In a crossed Claisen condensation, an ester without hydrogens serves as the electrophilic component.
Chapter 2248 Crossed Claisen Condensation with Ketones and Esters Crossed Claisen condensation between ketones and esters are also possible. Ketones are more acidic than esters, and the ketone component is more likely to deprotonate and serve as the enolate component in the condensation.
Chapter 2249 Crossed Claisen Mechanism The ketone enolate attacks the ester, which undergoes nucleophilic acyl substitution, and thereby, acylates the ketone.
Chapter 2250 Propose a mechanism for the self-condensation of ethyl acetate to give ethyl acetoacetate. The first step is formation of the ester enolate. The equilibrium for this step lies far to the left; ethoxide deprotonates only a small fraction of the ester. The enolate ion attacks another molecule of the ester; expulsion of ethoxide ion gives ethyl acetoacetate. Solved Problem 4 Solution
Chapter 2251 In the presence of ethoxide ion, ethyl acetoacetate is deprotonated to give its enolate. This exothermic deprotonation helps to drive the reaction to completion. When the reaction is complete, the enolate ion is reprotonated to give ethyl acetoacetate. Solved Problem 4 (Continued) Solution (Continued)
Chapter 2252 Show what ester would undergo Claisen condensation to give the following -keto ester. First, break the structure apart at the bond ( to the ester carbonyl). This is the bond formed in the Claisen condensation. Solved Problem 5 Solution
Chapter 2253 Next, replace the proton that was lost, and replace the alkoxy group that was lost from the carbonyl. Two molecules of methyl 3-phenylpropionate result. Now draw out the reaction. Sodium methoxide is used as the base because the reactants are methyl esters. Solved Problem 5 (Continued) Solution (Continued)
Chapter 2255 Malonic Ester Synthesis The malonic ester synthesis makes substituted derivatives of acetic acids. Malonic ester is alkylated or acylated on the carbon that is alpha to both carbonyl groups, and the resulting derivative is hydrolyzed and allowed to decarboxylate.
Chapter 2256 Decarboxylation of the Alkylmalonic Acid Decarboxylation takes place through a cyclic transition state, initially giving an enol form that quickly tautomerizes to the product.
Chapter 2259 Show how the malonic ester synthesis is used to prepare 2-benzylbutanoic acid. 2-Benzylbutanoic acid is a substituted acetic acid having the substituents Ph–CH 2 – and CH 3 CH 2 –. Adding these substituents to the enolate of malonic ester eventually gives the correct product. Solved Problem 6 Solution
Chapter 2260 Acetoacetic Ester Synthesis The acetoacetic ester synthesis is similar to the malonic ester synthesis, but the final products are ketones.
Chapter 2261 Alkylation of Acetoacetic Ester Ethoxide ion completely deprotonates acetoacetic ester. The resulting enolate is alkylated by an unhindered alkyl halide or tosylate to give an alkylacetoacetic ester.
Chapter 2262 Hydrolysis of Alkylacetoacetic Ester Acidic hydrolysis of the alkylacetoacetic ester initially gives an alkylacetoacetic acid, which is a -keto acid. The keto group in the -position promotes decarboxylation to form a substituted version of acetone.
Chapter 2263 Show how the acetoacetic ester synthesis is used to make 3-propylhex-5-en-2-one. The target compound is acetone with an n-propyl group and an allyl group as substituents: Solved Problem 7 Solution
Chapter 2264 Hydrolysis proceeds with decarboxylation to give the disubstituted acetone product. With an n-propyl halide and an allyl halide as the alkylating agents, the acetoacetic ester synthesis should produce 3-propyl-5-hexen-2-one. Two alkylation steps give the required substitution: Solved Problem 7 (Continued) Solution (Continued)
Chapter 2265 Conjugate Additions: The Michael Reaction , -unsaturated carbonyl compounds have unusually electrophilic double bonds. The -carbon is electrophilic because it shares the partial positive charge of the carbonyl carbon through resonance.
Chapter 2266 1,2-Addition and 1,4-Addition When attack occurs at the carbonyl group, protonation of the oxygen leads to a 1,2-addition. When attack occurs at the β-position, the oxygen atom is the fourth atom counting from the nucleophile, and the addition is called a 1,4-addition.
Chapter 2268 1,4-Addition of an Enolate to Methyl Vinyl Ketone (MVK) An enolate will do a 1,4-attack on the - unsaturated ketone (MVK).
Chapter 2269 Show how the following diketone might be synthesized using a Michael addition. A Michael addition would have formed a new bond at the carbon of the acceptor. Therefore, we break this molecule apart at the bond. Solved Problem 8 Solution
Chapter 2270 Robinson Annulation With enough base, the product of the Michael reaction undergoes a spontaneous intramolecular aldol condensation, usually with dehydration, to give a six-membered ring — a conjugated cyclohexenone.