Carbonyl Compounds III
Carbonyl Compounds III The Acidity of an α-Hydrogen • A hydrogen bonded to an sp3 carbon adjacent to a carbonyl carbon is much more acidic than hydrogen’s bonded to other sp3 carbons. • Carbon Acid: a compound that contains a relatively acidic hydrogen bonded to an sp3 carbon. • The α-hydrogen is more acidic because the base formed when a proton is removed from an α-carbon is more stable than a base formed when proton is removed from other sp3 carbons. o The electrons left behind when the proton is removed are delocalized and electron delocalization increases stability. o The electrons are delocalized onto the oxygen, an atom that is better able to accommodate them because it is more electronegative than carbon. • Aldehydes and ketones are more acidic than esters because the oxygen of the OR group of the ester also has a lone pair that can be delocalized onto the carbonyl oxygen (competes). • If the α-carbon is between two carbonyl groups, the acidity of an α-hydrogen is even greater because the electrons left behind when the proton is removed can be delocalized onto two oxygen atoms. Keto-Enol Tautomers • A ketone exists in equilibrium with its enol tautomer. • For most ketones, the enol tautomer (-OH and C=C) is much less stable than the keto tautomer (C=O). • The fraction of the enol tautomer in an aqueous solution is considerably greater for a β-diketone (acid anhydride) because the enol tautomer is stabilized by intramolecular hydrogen bonding and by conjugation of the carbon-carbon double bond with the second carbonyl group. • Phenol is an enol tautomer and is more stable than its keto tautomer because it is aromatic and the keto tautomer is not. Enolization • Keto-Enol Tautomerization or Enolization: interconversion of the keto and enol tautomers. • Mechanism for base-catalyzed keto-enol interconversion: o Hydroxide ion removes a proton from the α-carbon of the keto tautomer, forming an anion called an enolate ion. The enolate has two resonance contributors. o Protonation on oxygen forms the enol tautomer, whereas protonation on the α-carbon reforms the keto tautomer. • Mechanism for acid-catalyzed keto-enol interconversion: o The carbonyl oxygen of the keto tautomer is protonated. o Water removes a proton from the α-carbon, forming the enol. How Enols and Enolate Ions React • Carbonyl compounds with an α-hydrogen can undergo substitution reaction at the α-carbon. • Mechanism for base-catalyzed α-substitution: o A base removes a proton from the α-carbon, forming an enolate ion.
The enolate ion then reacts with an electrophile. Because they are negatlively charged, enolate ions are better nucleophiles than enols are. α-Substitution Reaction: one electrophile (E+) is substituted for another (H=) at the α-carbon. Mechanism for acid-catalyzed α-subsitution: o The acid protonates the most electron-dense atom in the compound. o Water removes a proton from the α-carbon. o The enol then reacts with an electrophile. o
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Ambident Nucleophile: a nucleophile with two nucleophilic sites (O- or C-). o Protonation occurs preferentially on oxygen because of the greater concentration of negative charge on the more electronegative atom. o When the electrophile is something other than a proton, carbon is more likely to be the nucleophile because carbon is better nucleophile than oxygen.
Halogenation of the α-Carbon of Aldehydes and Ketons • When Br2, Cl2 or I2 is added to a solution of an aldehyde or keton, a halogen replaces one or more of the α-hydrogens of the carbonyl compound. • Under acidic conditions, one α-hydrogen is substituted for a halogen. • Mechanism for acid-catalyzed halogenation: o The carbonyl oxygen is protonated. o Water removes a proton from the α-carbon, forming an enol. o The enol reacts with an electrophilic halogen.
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Under basic conditions, all the α-hydrogens are substituted for halogens. Mechanism for base-promoted halogenation: o Hydroxide ion removes a proton from the α-carbon. o The enolate ion reacts with the electrophilic bromine. o These two steps are repeated until all the α-hydrogens are replaced by the halogen. Each successive halogenation is more rapid than the previous one because the electron-withdrawing halogen increases the acidity of remaining α-hydrogens (in basic conditions). Under acidic conditions, each successive halogenation is slower than the previous one because the electron-withdrawing halogen decreases the basicity of the carbonyl oxygen. In the presence of excess base and excess halogen, a methyl ketone is converted into a carboxylate ion. Mechanism for the haloform reaction: o First, all the hydrogens of the methyl group are replated by lahogens, forming a tri-halo-substituted ketone. o Hydroxide ion attacks the carbonyl carbon of the trihalo-substituted ketone. o Because the trihalomethyl ion is weaker base than hydroxide ion, the trihalomethyl ion is the group more easily expelled from the tetrahedral intermediate, forming a carboxylic acid. o Proton transfer form a carboxylate ion and a haloform (CHI3, CHCl3 or CHBr3).
Halogenation of the α-Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski Reaction • Carboxylic acids cannot undergo substitution reactions at the α-carbon because
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a base will remove the proton from the OH group instead of from the α-carbon, since OH is more acidic. Hell-Volhard-Zelinski Reaction (HVZ Reaction): if a carboxylic acid is treated with PBr3 and Br2, the α-carbon can be brominated. Mechanism for HVZ reaction: o PBr3 converts the carboxylic acid into an acyl bromide. o The acyl bromide is in equilibrium with its enol. o Bromination of the enol forms the α-brominated acyl bromide, which is hydrolyzed to the α-brominated carboxylic acid.
α-Halogenated Carbonyl Compounds Are Useful in Synthesis • When a base removes a proton from an α-carbon, the α-carbon because nucleophilic. • When the α-position is halogenated, the α-carbon becomes electrophlic. • α-brominated carbonyl compounds are useful to synthetic chemists because once a bromince has been introducted into the α-position of a carbonyl compound, a α,β-unsaturated carbonyl compound can be prepared by E2 elimination using tert-BuO-. Using LDA to Form an Enolate Ion • When hydroxide ion is used to remove an α-hydrogen from cyclohexanone, only a small amount of the carbonyl compound is converted into the enolate ion because hydroxide ion is a weaker base than the base being formed. • Lithium Diisopropylamide (LDA) is used to remove the α-hydrogen, essentially all the carbonyl compound is converted to the enolate ion because LDA is a much stronger base than the base being formed. • LDA is the base of choice for reactions that require the carbonyl compound to be completely converted to an enolate ion before it reacts with an electrophile. • LDA is a strong base but a poor nucleophile, it removes an α-hydrogen much faster than it attacks a carbonyl carbon. Alkylation of the α-Carbon of Carbonyl Compounds • Enolate ions can be alkylated on the α-carbon. • Alkylation is carried out by first removing a proton from the α-carbon with a strong base like LDA and then adding the appropriate alkyl halide. • Because the alkylation is an SN2 reaction, it works best with methyl halides and primary alkyl halides. • This method can be used to alkylate ketones, esters and nitriles at the α-carbon but aldehydes give poor yields of α-alkylated products. • When the ketone is not symmetrical, either α-carbon can be alkylated and two products will form, depending on the reaction conditions. • The less substituted α-carbon can be alkylated without having to control the conditions by first making the N,N-dimethylhydrazone of the ketone. Alkylation and Acylation of the α-Carbon Using an Enamine Intermediate • Enamine: formed when an aldehyde or a ketone reacts with a secondary amine. • Enamines react with electrophiles in the same way that enolate ions do. • Electrophiles can be added to the α-carbon of an aldehyde or a ketone by: o First, converting the carbonyl compound to an enamine. o Then, adding the electrophile (primary or methyl alkyl or acyl halides).
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Finally, hydrolyzing the imine back to the ketone.
The α-carbon of an aldehyde or a ketone can be made to react with an electrophile either by first treating the carbonyl compound with LDA or by converting it into an enamine. The α-carbon of an aldehyde or a ketone can be made to react with a nucleophile by first brominating the α-position of the carbonyl compound.
Alkylation of the β-Carbon: The Michael Reaction • Michael Reaction: the addition reaction when the nucleophile is an enolate ion. • Enolate ions that work best are those that are flanked by two electronwithdrawing groups because they are weak bases and addition occurs at the βcarbon. • If a carbonyl carbon of the enolate ion is given the 1-position, the carbonyl carbon of the other reactant is at the 5-position. • Mechanism for the Michael reaction: o A base removes a proton from the α-carbon of the carbon acid. o The enolate ion adds to the β-carbon of an α,β-unsaturated carbonyl compound. o The α-carbon obtains a proton from the solvent.
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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. Stork Enamine Reaction: when an enamine is used as a nucleophile in a Michael reaction.
An Aldol Addition Forms β-Hydroxyaldehydes or β-Hydroxyketones • Aldol Addition: one polecule of a carbonyl compound (after a proton is removed from an α-carbon) reacts as a nucleophile and attacks the electrophilic carbonyl carbon of a second molecule of the carbonyl compound. • Aldol addition is a reaction between two molecules of aldehyde or two molecules of a ketone. • When the reactant is an aldehyde, the product is a β-hydroxyaldehyde. • When the reactant is a ketone, the product is a β-hydroxyketone. • The new C-C bond formed in an aldol addition connects the α-carbon of one molecule and the carbon that formerly was the carbonyl carbon of the other molecule. • Mechanism for aldol addition: o A base removes a proton from the α-carbon, creating an enolate ion. o The enolate ion adds to the carbonyl carbon of a second molecule of the carbonyl compound. o The negatively charged oxygen is protonated by the solvent. • Because an aldol addition reaction occurs between two molecules of the same carbonyl compound, the product has twice as many carbons as the reacting aldehyde or ketone. • Ketones are less susceptible than aldehydes to attack by nucleophiles so aldol additions occur more slowly with ketones. Dehydration of Aldol Addition Products Forms α,β-Unsaturated Aldehydes and Ketones • Aldol Condensation: the overall reaction if the product of an aldol addition undergoes dehydration. • Condensation Reaction: a reaction that combines two molecules by forming a
new C-C bond while removing a small molecule (usually water or an alcohol). The Mixed Aldol Addition • Mixed Aldol Addition or Crossed Aldol Addition: if two different carbonyl compounds are used in an aldol addition, four products can be formed because each enolate ion can react with either of the two carbonyl compounds. • If one of the carbonyl compounds does not have any α-hydrogens, it cannot form an enolate ion; this reduces the number of possible products from four to two. • A greater amount of one of the two products will be formed if the compound without α-hydrogens is always present in excess because then the enolate ion will be more likely to react with it, rather than with another molecule of the enolate ion’s parent compound. A Claisen Condensation Forms a β-Keto Ester • Claisen Condensation: when two molecules of an ester undergo a condensation reaction. • After nucleophilic attack, the negatively charged oxygen reforms the carbonoxygen double bond and expels the –OR group. • The Claisen condensation is a nucleophilic acyl substitution reaction, whereas the aldol addition is a nucleophilic addition reaction. The Mixed Claisen Condensation • Mixed Claisen Condensation: a condensation reaction between two different esters. • One product will be formed if one of the esters has no α-hydrogens and the other ester is added slowly so that the ester without α-hydrogens is always in excess. • In the condensation of a ketone and an ester, one product is formed if the ketone and the base are both added slowly to the ester, giving the β-diketone product. Intramolecular Condensation and Addition Reactions • An intramolecular reaction readily occurs if the reaction leads to the formation of five or six-membered rings. • Dieckmann Condensation: an intramolecular Claisen condensation of two esters. • Robinson Annulation: a reaction that puts two carbon-carbon bond-forming reactions together, providing a route to the synthesis of many organic molecules. o The first stage of a Robinson annulation is a Michael reaction that forms a 1,5-diketone. o The second stage is an intramolecular aldol addition. o Heating the basic solution dehydrates the alcohol. • Annulation Reaction: a ring-forming reaction. 3-Oxocarboxylic Acid Can Be Decarboxylated • If the CO2 group is bonded to a carbon adjacent to an carbonyl carbon, the CO2 group can be removed because the electrons left behind can be delocalized onto the carbonyl oxygen. • Decarboxylation: loss of CO2 from a molecule. • 3-oxocarboxylic acids (carboxylic acids with a carbonyl group at the 3-position)
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decarboxylate when heated. Decarboxylation is easier if the reaction is carried out under acidic conditions because the reaction is catalyzed by an intramolecular transfer of a proton from the carboxyl group to the carbonyl oxygen.
The Malonic Ester Synthesis: A Way to Synthesize a Carboxylic Acid • Malonic Ester Synthesis: forms a carboxylic acid with two more carbon atoms than the alkyl halide. • Mechanism for the Malonic Ester Synthesis: o A proton is easily removed from the α-carbon because it is flanked by two ester groups. o The resulting α-carbanion reacts with an alkyl halide, forming an αsubstituted malonic ester. Because alkylation is an SN2 reaction, it works best with primary alkyl halides and methyl halides. o Heating the α-substituted malonic ester in an acidic aqueous solution hydrolyzes both ester groups to carboxylic acid groups, forming an αsubstituted malonic acid. o Further heating decarboxylates the 3-oxocarboxylic acid.
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Carboxylic acids with two substituents bonded to the α-carbon can be prepared by carrying out two successive α-carbon alkylations.
The Acetoacetic Ester Synthesis: A Way to Synthesize a Methyl Ketone • Acetoacetic Ester Synthesis: forms a methyl ketone with two more carbon atoms than the alkyl halide. • The last step in the acetoacetic ester synthesis is the decarboxylation of a substituted acetoacetic acid rather than a substituted malonic acid. Designing a Synthesis VII: Making New Carbon-Carbon Bonds • First locate the new bond that must be made. • Determine which of the atoms that form the bond should be the nucleophile and which should be the electrophile. • Determine what compound you could use that would give you the desired electrophilic and nucleophilic sites. • The α-hydrogens of the ketone are more acidic than the α-hydrogens of the ester.
The enolate ion then reacts with an electrophile. Because they are negatlively charged, enolate ions are better nucleophiles than enols are. α-Substitution Reaction: one electrophile (E+) is substituted for another (H=) at the α-carbon. Mechanism for acid-catalyzed α-subsitution: o The acid protonates the most electron-dense atom in the compound. o Water removes a proton from the α-carbon. o The enol then reacts with an electrophile. o
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Ambident Nucleophile: a nucleophile with two nucleophilic sites (O- or C-). o Protonation occurs preferentially on oxygen because of the greater concentration of negative charge on the more electronegative atom. o When the electrophile is something other than a proton, carbon is more likely to be the nucleophile because carbon is better nucleophile than oxygen.
Halogenation of the α-Carbon of Aldehydes and Ketons • When Br2, Cl2 or I2 is added to a solution of an aldehyde or keton, a halogen replaces one or more of the α-hydrogens of the carbonyl compound. • Under acidic conditions, one α-hydrogen is substituted for a halogen. • Mechanism for acid-catalyzed halogenation: o The carbonyl oxygen is protonated. o Water removes a proton from the α-carbon, forming an enol. o The enol reacts with an electrophilic halogen.
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Under basic conditions, all the α-hydrogens are substituted for halogens. Mechanism for base-promoted halogenation: o Hydroxide ion removes a proton from the α-carbon. o The enolate ion reacts with the electrophilic bromine. o These two steps are repeated until all the α-hydrogens are replaced by the halogen. Each successive halogenation is more rapid than the previous one because the electron-withdrawing halogen increases the acidity of remaining α-hydrogens (in basic conditions). Under acidic conditions, each successive halogenation is slower than the previous one because the electron-withdrawing halogen decreases the basicity of the carbonyl oxygen. In the presence of excess base and excess halogen, a methyl ketone is converted into a carboxylate ion. Mechanism for the haloform reaction: o First, all the hydrogens of the methyl group are replated by lahogens, forming a tri-halo-substituted ketone. o Hydroxide ion attacks the carbonyl carbon of the trihalo-substituted ketone. o Because the trihalomethyl ion is weaker base than hydroxide ion, the trihalomethyl ion is the group more easily expelled from the tetrahedral intermediate, forming a carboxylic acid. o Proton transfer form a carboxylate ion and a haloform (CHI3, CHCl3 or CHBr3).
Halogenation of the α-Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski Reaction • Carboxylic acids cannot undergo substitution reactions at the α-carbon because
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a base will remove the proton from the OH group instead of from the α-carbon, since OH is more acidic. Hell-Volhard-Zelinski Reaction (HVZ Reaction): if a carboxylic acid is treated with PBr3 and Br2, the α-carbon can be brominated. Mechanism for HVZ reaction: o PBr3 converts the carboxylic acid into an acyl bromide. o The acyl bromide is in equilibrium with its enol. o Bromination of the enol forms the α-brominated acyl bromide, which is hydrolyzed to the α-brominated carboxylic acid.
α-Halogenated Carbonyl Compounds Are Useful in Synthesis • When a base removes a proton from an α-carbon, the α-carbon because nucleophilic. • When the α-position is halogenated, the α-carbon becomes electrophlic. • α-brominated carbonyl compounds are useful to synthetic chemists because once a bromince has been introducted into the α-position of a carbonyl compound, a α,β-unsaturated carbonyl compound can be prepared by E2 elimination using tert-BuO-. Using LDA to Form an Enolate Ion • When hydroxide ion is used to remove an α-hydrogen from cyclohexanone, only a small amount of the carbonyl compound is converted into the enolate ion because hydroxide ion is a weaker base than the base being formed. • Lithium Diisopropylamide (LDA) is used to remove the α-hydrogen, essentially all the carbonyl compound is converted to the enolate ion because LDA is a much stronger base than the base being formed. • LDA is the base of choice for reactions that require the carbonyl compound to be completely converted to an enolate ion before it reacts with an electrophile. • LDA is a strong base but a poor nucleophile, it removes an α-hydrogen much faster than it attacks a carbonyl carbon. Alkylation of the α-Carbon of Carbonyl Compounds • Enolate ions can be alkylated on the α-carbon. • Alkylation is carried out by first removing a proton from the α-carbon with a strong base like LDA and then adding the appropriate alkyl halide. • Because the alkylation is an SN2 reaction, it works best with methyl halides and primary alkyl halides. • This method can be used to alkylate ketones, esters and nitriles at the α-carbon but aldehydes give poor yields of α-alkylated products. • When the ketone is not symmetrical, either α-carbon can be alkylated and two products will form, depending on the reaction conditions. • The less substituted α-carbon can be alkylated without having to control the conditions by first making the N,N-dimethylhydrazone of the ketone. Alkylation and Acylation of the α-Carbon Using an Enamine Intermediate • Enamine: formed when an aldehyde or a ketone reacts with a secondary amine. • Enamines react with electrophiles in the same way that enolate ions do. • Electrophiles can be added to the α-carbon of an aldehyde or a ketone by: o First, converting the carbonyl compound to an enamine. o Then, adding the electrophile (primary or methyl alkyl or acyl halides).
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Finally, hydrolyzing the imine back to the ketone.
The α-carbon of an aldehyde or a ketone can be made to react with an electrophile either by first treating the carbonyl compound with LDA or by converting it into an enamine. The α-carbon of an aldehyde or a ketone can be made to react with a nucleophile by first brominating the α-position of the carbonyl compound.
Alkylation of the β-Carbon: The Michael Reaction • Michael Reaction: the addition reaction when the nucleophile is an enolate ion. • Enolate ions that work best are those that are flanked by two electronwithdrawing groups because they are weak bases and addition occurs at the βcarbon. • If a carbonyl carbon of the enolate ion is given the 1-position, the carbonyl carbon of the other reactant is at the 5-position. • Mechanism for the Michael reaction: o A base removes a proton from the α-carbon of the carbon acid. o The enolate ion adds to the β-carbon of an α,β-unsaturated carbonyl compound. o The α-carbon obtains a proton from the solvent.
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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. Stork Enamine Reaction: when an enamine is used as a nucleophile in a Michael reaction.
An Aldol Addition Forms β-Hydroxyaldehydes or β-Hydroxyketones • Aldol Addition: one polecule of a carbonyl compound (after a proton is removed from an α-carbon) reacts as a nucleophile and attacks the electrophilic carbonyl carbon of a second molecule of the carbonyl compound. • Aldol addition is a reaction between two molecules of aldehyde or two molecules of a ketone. • When the reactant is an aldehyde, the product is a β-hydroxyaldehyde. • When the reactant is a ketone, the product is a β-hydroxyketone. • The new C-C bond formed in an aldol addition connects the α-carbon of one molecule and the carbon that formerly was the carbonyl carbon of the other molecule. • Mechanism for aldol addition: o A base removes a proton from the α-carbon, creating an enolate ion. o The enolate ion adds to the carbonyl carbon of a second molecule of the carbonyl compound. o The negatively charged oxygen is protonated by the solvent. • Because an aldol addition reaction occurs between two molecules of the same carbonyl compound, the product has twice as many carbons as the reacting aldehyde or ketone. • Ketones are less susceptible than aldehydes to attack by nucleophiles so aldol additions occur more slowly with ketones. Dehydration of Aldol Addition Products Forms α,β-Unsaturated Aldehydes and Ketones • Aldol Condensation: the overall reaction if the product of an aldol addition undergoes dehydration. • Condensation Reaction: a reaction that combines two molecules by forming a
new C-C bond while removing a small molecule (usually water or an alcohol). The Mixed Aldol Addition • Mixed Aldol Addition or Crossed Aldol Addition: if two different carbonyl compounds are used in an aldol addition, four products can be formed because each enolate ion can react with either of the two carbonyl compounds. • If one of the carbonyl compounds does not have any α-hydrogens, it cannot form an enolate ion; this reduces the number of possible products from four to two. • A greater amount of one of the two products will be formed if the compound without α-hydrogens is always present in excess because then the enolate ion will be more likely to react with it, rather than with another molecule of the enolate ion’s parent compound. A Claisen Condensation Forms a β-Keto Ester • Claisen Condensation: when two molecules of an ester undergo a condensation reaction. • After nucleophilic attack, the negatively charged oxygen reforms the carbonoxygen double bond and expels the –OR group. • The Claisen condensation is a nucleophilic acyl substitution reaction, whereas the aldol addition is a nucleophilic addition reaction. The Mixed Claisen Condensation • Mixed Claisen Condensation: a condensation reaction between two different esters. • One product will be formed if one of the esters has no α-hydrogens and the other ester is added slowly so that the ester without α-hydrogens is always in excess. • In the condensation of a ketone and an ester, one product is formed if the ketone and the base are both added slowly to the ester, giving the β-diketone product. Intramolecular Condensation and Addition Reactions • An intramolecular reaction readily occurs if the reaction leads to the formation of five or six-membered rings. • Dieckmann Condensation: an intramolecular Claisen condensation of two esters. • Robinson Annulation: a reaction that puts two carbon-carbon bond-forming reactions together, providing a route to the synthesis of many organic molecules. o The first stage of a Robinson annulation is a Michael reaction that forms a 1,5-diketone. o The second stage is an intramolecular aldol addition. o Heating the basic solution dehydrates the alcohol. • Annulation Reaction: a ring-forming reaction. 3-Oxocarboxylic Acid Can Be Decarboxylated • If the CO2 group is bonded to a carbon adjacent to an carbonyl carbon, the CO2 group can be removed because the electrons left behind can be delocalized onto the carbonyl oxygen. • Decarboxylation: loss of CO2 from a molecule. • 3-oxocarboxylic acids (carboxylic acids with a carbonyl group at the 3-position)
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decarboxylate when heated. Decarboxylation is easier if the reaction is carried out under acidic conditions because the reaction is catalyzed by an intramolecular transfer of a proton from the carboxyl group to the carbonyl oxygen.
The Malonic Ester Synthesis: A Way to Synthesize a Carboxylic Acid • Malonic Ester Synthesis: forms a carboxylic acid with two more carbon atoms than the alkyl halide. • Mechanism for the Malonic Ester Synthesis: o A proton is easily removed from the α-carbon because it is flanked by two ester groups. o The resulting α-carbanion reacts with an alkyl halide, forming an αsubstituted malonic ester. Because alkylation is an SN2 reaction, it works best with primary alkyl halides and methyl halides. o Heating the α-substituted malonic ester in an acidic aqueous solution hydrolyzes both ester groups to carboxylic acid groups, forming an αsubstituted malonic acid. o Further heating decarboxylates the 3-oxocarboxylic acid.
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Carboxylic acids with two substituents bonded to the α-carbon can be prepared by carrying out two successive α-carbon alkylations.
The Acetoacetic Ester Synthesis: A Way to Synthesize a Methyl Ketone • Acetoacetic Ester Synthesis: forms a methyl ketone with two more carbon atoms than the alkyl halide. • The last step in the acetoacetic ester synthesis is the decarboxylation of a substituted acetoacetic acid rather than a substituted malonic acid. Designing a Synthesis VII: Making New Carbon-Carbon Bonds • First locate the new bond that must be made. • Determine which of the atoms that form the bond should be the nucleophile and which should be the electrophile. • Determine what compound you could use that would give you the desired electrophilic and nucleophilic sites. • The α-hydrogens of the ketone are more acidic than the α-hydrogens of the ester.
