Carbonyl Alpha Substitution Reactions
Chapter 22: Carbonyl Alpha Substitution Reactions
CHM247H1 Jasmyn Lee
22.1 Keto-Enol Tautomerism The position next to a point of reference is the alpha (α) position
An electrophile (E+) can be substituted for an α H
Tautomers – the spontaneous interconversion between two isomers; usually with the change in position of a hydrogen o Keto and enol isomers are tautomers Tautomers vs. Isomers o Tautomers – constitutional isomers; different compounds with different structures Have atoms arranged differently o Resonance Forms – different representations of a single compound Differ only in position of π and non-bonding electrons The reaction proceeds by way of
o o
Electron rich intermediates form new C-C bond with E+ Enol is more electron rich than alkene, because OH has a powerful electron donating resonance effect
Keto and enol forms are tautomers of the carbonyl group in equilibrium with each other tautomers differ in the position of “=” and H atom
Enol form is difficult to isolate – must be stabilized by conjugation or by intermolecular hydrogen bonding o Enol formation is catalyzed by acid and base In β-dicarbonyl compounds the enol form predominates o
The enol form is stabilized by conjugation and intermolecular Hydrogen bonding, especially as a 6membered ring Acid Catalyzed Enol Formation 1. Protonation occurs first – forms a resonance stabilized carbocation 2. The proton is them removed – forms the enol o
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CHM247H1 Jasmyn Lee
Base Catalyzed Enol Formation 1. α proton is removed first – forms a resonance stabilized enolate 2. Enolate picks up a proton from water – forms the enol
22.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions Like alkenes, enols react with electrophiles Electron donation from HO makes them more reactive than alkenes
Examples of enol reactivity 22.3 Alpha Halogenation of Aldehydes and Ketones α – halogenation of aldehydes and ketones – acid catalyzed
Also works well with Cl2 and I2 Mechanism of Acid Catalyzed α Substitution o Slow, rate determining formation of enol o Then fast nucleophilic attack on halogen and deprotonation
Rate = k [ketone] [H+] (no halogen term) o i.e. enol formation is rate determining o α – bromination, α – chlorination, α – iodination; all proceed at the same rate To substitute deuterium, use D3O+
22.4 α-Bromination of Carboxylic Acids α-bromination of carbonyl compounds by Br2 in acetic acid is limited to aldehydes and ketones o α-bromination goes by an enolate mechanism but carboxylic acid, esters and amides don’t form enolate Carboxylic acids can be α brominated by a mixture of PBr3 and Br2 (Hell-Volhard-Zelinkski) The Hell-Volhard-Zelinski Reaction
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o
First step: Formation of Acid Halide
CHM247H1 Jasmyn Lee
22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation Comparing Acidity of Different Kinds of Protons A hydrogen on the α position of a carbonyl compound is weakly acidic and can be removed by a strong base to yield an enolate ion Compares pKa values
Acidity of a proton is increased by 1. Resonance stabilization 2. Negative charge on O in the conjugate base
Enolate can be formed from esters, 3° amides (less acidic) and nitriles
Protons α to two carbonyl groups are especially acidic o Three resonance contributors o Resonance delocalizes the negative charge on two different oxygen atoms
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CHM247H1 Jasmyn Lee Common bases used to form enolate
Stronger base drives equilibrium to enolate side because enolate formation is an acid-base equilibrium To form an enolate in essentially 100% yield need a strong non-nucleophilic base to deprotonate carbonyl compound o Lithium diisopropyl amide o A strong, bulky base, not nucleophilic o Wont add to carbonyl
All three alkylation’s subject to usual SN2 restrictions
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22.6 Reactivity of Enolate Ions Enolate ions are more useful than enols 1. Enolate ions can be prepared and isolated; enols are only short-lived intermediates 2. Enolates are more reactive than enols and undergo many reactions that enols do not o Enols – neutral o Enolate – negative charge Enolate ions are looked at either as vinylic alkoxide or as α-keto carbanions As nucleophiles, enolates react with many electrophiles Resonance stabilized enolate has two potential reaction sites – oxygen or
CHM247H1 Jasmyn Lee
carbon
Usually reacts at Carbon end; this site is more nucleophilic
(used to be under 22.4)
Base Promoted α-halogenation Aldehydes and ketones undergo base-promoted α-halogenation Even relatively weak bases, are effective for halogenation o It is not necessary to convert the ketone completely into its enolate ion o Halogen reacts with small amount of enolate immediately – removes it from the reaction; drives the equilibrium toward further enolate ion formation In base, can’t stop α-halogenation after 1st substitution The electron withdrawing inductive effect of the –X stabilizes the second enolate o α-halogenated ketone is more acidic than starting ketone because of electron withdrawing inductive effects of halogen atom o Monohalogenated products are rapidly turned into enolate ions and further halogenated Haloform Reaction o Haloform is made from α-methyl ketones and α-methyl alcohols
o
Haloform Mechanism
o Iodoform If X = I product = CHI3 (iodoform), o A yellow solid, easily identified by m.p. I3C:- is a good leaving group (unusual for a carbanion)
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CHM247H1 Jasmyn Lee
22.7 Alkylate of Enolate Ions Treatment with an alkyl halide or tosylate Forms new C-C bond Alkylation occurs when nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction and displaces the leaving group by backside attack Leaving group, -X, in alkylating agent can be Cl, Br, I, or Tos Alkyl group, R, should be 1°° or methyl – preferably benzylic or vinylic o 2° halides react poorly o 3° halides do not react at all – competing E2 elimination of HX occurs instead o Vinylic and aryl halides are unreactive – backside approach is sterically prevented Malonic Ester Synthesis Method for preparing a carboxylic acid from an alkyl halide, while lengthening the carbon chain by 2 atoms
Mechanism
Malonic ester is relatively acidic (pKa=13) – αhydrogen’s are flanked by two carbonyl groups Malonic Ester is easily converted into enolate ion by reaction with NaOEt in ethanol Enolate is good Nu: - reacts rapidly with an alkyl halide to give an α-substituted malonic ester Alkylation process repeats to yield a dialkylated malonic ester On heating with aqueous hydrochloric acid, the (di)alkylated malonic ester undergoes hydrolysis of its two ester groups followed by decarboxylation (loss of CO2) to yield a substituted monocarboxylic acid o
Must add both groups before decarboxylation – decarboxylation is unique to compounds that have a second carbonyl group two atoms away from the -COOH Can substitute a different alkyl group for each α-H
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CHM247H1 Jasmyn Lee
Method can be used to make cyclohexane carboxylic acids
Fatty Acid Biosynthesis Goes By a Malonic Ester Mechanism (enzyme catalyzed)
Analyze the Product to Determine the Starting Materials for the Malonic Ester Synthesis 1. Locate the carbon α to COOH O OH 2. Separate into components RX and CH2(COOEt)2 HO
O
Acetoacetic Ester Synthesis Converts an alkyl halide into am ethyl ketone having three more carbons
Mechanism parallels that of malonic ester synthesis o Acetoacetic ester α-hydrogen’s are flanked by two carbonyl groups – readily converted into its enolate ion o enolate ion alkylated by reaction with an alkyl halide o second alkylation can also be carried out if desired – has two acidic α-hydrogen’s o on heating with aqueous HCl, the (di)alkylated acetoacetic ester is hydrolyzed to a β-keto acid, which undergoes decarboxylation o decarboxylation involved ketone enol as initial product Can add 2 (different) R groups Three step sequence 1) enolate ion formation, 2) alkylation, 3) hydrolysis/decarboxylation o Is applicable to all β-keto esters with acidic α-hydrogen’s
Practice: Show How the Acetoacetic Ester Synthesis is Used to Make 3-propylhex-5-en-2-one Explain why the compound at right cannot be made by acetoacetic ester synthesis Show how it may be made from 1,3-diphenylacetone o Using LDA o Using an Enamine
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CHM247H1 Jasmyn Lee
22.1 Keto-Enol Tautomerism The position next to a point of reference is the alpha (α) position
An electrophile (E+) can be substituted for an α H
Tautomers – the spontaneous interconversion between two isomers; usually with the change in position of a hydrogen o Keto and enol isomers are tautomers Tautomers vs. Isomers o Tautomers – constitutional isomers; different compounds with different structures Have atoms arranged differently o Resonance Forms – different representations of a single compound Differ only in position of π and non-bonding electrons The reaction proceeds by way of
o o
Electron rich intermediates form new C-C bond with E+ Enol is more electron rich than alkene, because OH has a powerful electron donating resonance effect
Keto and enol forms are tautomers of the carbonyl group in equilibrium with each other tautomers differ in the position of “=” and H atom
Enol form is difficult to isolate – must be stabilized by conjugation or by intermolecular hydrogen bonding o Enol formation is catalyzed by acid and base In β-dicarbonyl compounds the enol form predominates o
The enol form is stabilized by conjugation and intermolecular Hydrogen bonding, especially as a 6membered ring Acid Catalyzed Enol Formation 1. Protonation occurs first – forms a resonance stabilized carbocation 2. The proton is them removed – forms the enol o
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CHM247H1 Jasmyn Lee
Base Catalyzed Enol Formation 1. α proton is removed first – forms a resonance stabilized enolate 2. Enolate picks up a proton from water – forms the enol
22.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions Like alkenes, enols react with electrophiles Electron donation from HO makes them more reactive than alkenes
Examples of enol reactivity 22.3 Alpha Halogenation of Aldehydes and Ketones α – halogenation of aldehydes and ketones – acid catalyzed
Also works well with Cl2 and I2 Mechanism of Acid Catalyzed α Substitution o Slow, rate determining formation of enol o Then fast nucleophilic attack on halogen and deprotonation
Rate = k [ketone] [H+] (no halogen term) o i.e. enol formation is rate determining o α – bromination, α – chlorination, α – iodination; all proceed at the same rate To substitute deuterium, use D3O+
22.4 α-Bromination of Carboxylic Acids α-bromination of carbonyl compounds by Br2 in acetic acid is limited to aldehydes and ketones o α-bromination goes by an enolate mechanism but carboxylic acid, esters and amides don’t form enolate Carboxylic acids can be α brominated by a mixture of PBr3 and Br2 (Hell-Volhard-Zelinkski) The Hell-Volhard-Zelinski Reaction
2
o
First step: Formation of Acid Halide
CHM247H1 Jasmyn Lee
22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation Comparing Acidity of Different Kinds of Protons A hydrogen on the α position of a carbonyl compound is weakly acidic and can be removed by a strong base to yield an enolate ion Compares pKa values
Acidity of a proton is increased by 1. Resonance stabilization 2. Negative charge on O in the conjugate base
Enolate can be formed from esters, 3° amides (less acidic) and nitriles
Protons α to two carbonyl groups are especially acidic o Three resonance contributors o Resonance delocalizes the negative charge on two different oxygen atoms
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CHM247H1 Jasmyn Lee Common bases used to form enolate
Stronger base drives equilibrium to enolate side because enolate formation is an acid-base equilibrium To form an enolate in essentially 100% yield need a strong non-nucleophilic base to deprotonate carbonyl compound o Lithium diisopropyl amide o A strong, bulky base, not nucleophilic o Wont add to carbonyl
All three alkylation’s subject to usual SN2 restrictions
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22.6 Reactivity of Enolate Ions Enolate ions are more useful than enols 1. Enolate ions can be prepared and isolated; enols are only short-lived intermediates 2. Enolates are more reactive than enols and undergo many reactions that enols do not o Enols – neutral o Enolate – negative charge Enolate ions are looked at either as vinylic alkoxide or as α-keto carbanions As nucleophiles, enolates react with many electrophiles Resonance stabilized enolate has two potential reaction sites – oxygen or
CHM247H1 Jasmyn Lee
carbon
Usually reacts at Carbon end; this site is more nucleophilic
(used to be under 22.4)
Base Promoted α-halogenation Aldehydes and ketones undergo base-promoted α-halogenation Even relatively weak bases, are effective for halogenation o It is not necessary to convert the ketone completely into its enolate ion o Halogen reacts with small amount of enolate immediately – removes it from the reaction; drives the equilibrium toward further enolate ion formation In base, can’t stop α-halogenation after 1st substitution The electron withdrawing inductive effect of the –X stabilizes the second enolate o α-halogenated ketone is more acidic than starting ketone because of electron withdrawing inductive effects of halogen atom o Monohalogenated products are rapidly turned into enolate ions and further halogenated Haloform Reaction o Haloform is made from α-methyl ketones and α-methyl alcohols
o
Haloform Mechanism
o Iodoform If X = I product = CHI3 (iodoform), o A yellow solid, easily identified by m.p. I3C:- is a good leaving group (unusual for a carbanion)
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CHM247H1 Jasmyn Lee
22.7 Alkylate of Enolate Ions Treatment with an alkyl halide or tosylate Forms new C-C bond Alkylation occurs when nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction and displaces the leaving group by backside attack Leaving group, -X, in alkylating agent can be Cl, Br, I, or Tos Alkyl group, R, should be 1°° or methyl – preferably benzylic or vinylic o 2° halides react poorly o 3° halides do not react at all – competing E2 elimination of HX occurs instead o Vinylic and aryl halides are unreactive – backside approach is sterically prevented Malonic Ester Synthesis Method for preparing a carboxylic acid from an alkyl halide, while lengthening the carbon chain by 2 atoms
Mechanism
Malonic ester is relatively acidic (pKa=13) – αhydrogen’s are flanked by two carbonyl groups Malonic Ester is easily converted into enolate ion by reaction with NaOEt in ethanol Enolate is good Nu: - reacts rapidly with an alkyl halide to give an α-substituted malonic ester Alkylation process repeats to yield a dialkylated malonic ester On heating with aqueous hydrochloric acid, the (di)alkylated malonic ester undergoes hydrolysis of its two ester groups followed by decarboxylation (loss of CO2) to yield a substituted monocarboxylic acid o
Must add both groups before decarboxylation – decarboxylation is unique to compounds that have a second carbonyl group two atoms away from the -COOH Can substitute a different alkyl group for each α-H
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CHM247H1 Jasmyn Lee
Method can be used to make cyclohexane carboxylic acids
Fatty Acid Biosynthesis Goes By a Malonic Ester Mechanism (enzyme catalyzed)
Analyze the Product to Determine the Starting Materials for the Malonic Ester Synthesis 1. Locate the carbon α to COOH O OH 2. Separate into components RX and CH2(COOEt)2 HO
O
Acetoacetic Ester Synthesis Converts an alkyl halide into am ethyl ketone having three more carbons
Mechanism parallels that of malonic ester synthesis o Acetoacetic ester α-hydrogen’s are flanked by two carbonyl groups – readily converted into its enolate ion o enolate ion alkylated by reaction with an alkyl halide o second alkylation can also be carried out if desired – has two acidic α-hydrogen’s o on heating with aqueous HCl, the (di)alkylated acetoacetic ester is hydrolyzed to a β-keto acid, which undergoes decarboxylation o decarboxylation involved ketone enol as initial product Can add 2 (different) R groups Three step sequence 1) enolate ion formation, 2) alkylation, 3) hydrolysis/decarboxylation o Is applicable to all β-keto esters with acidic α-hydrogen’s
Practice: Show How the Acetoacetic Ester Synthesis is Used to Make 3-propylhex-5-en-2-one Explain why the compound at right cannot be made by acetoacetic ester synthesis Show how it may be made from 1,3-diphenylacetone o Using LDA o Using an Enamine
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