cn>chapter 22ct>carbonyl alpha-substitution reactions

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7/3/2017 1 Chapter 22 Carbonyl Alpha-Substitution Reactions Electrophilic substitution reactions of carbonyl-containing compounds 1 The Position The carbon next to the carbonyl group is designated as being in the position, hence called the alpha ( ) carbon Electrophilic substitution occurs at this position through either an enol or enolate ion 2 Alpha Substitution Alpha substitution is the substitution (in most cases) of one of the hydrogens attached to the alpha-carbon for an electrophile. The reaction occurs through an enol/enolate ion intermediate. 3

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CN>Chapter 22CT>Carbonyl Alpha-Substitution ReactionsElectrophilic substitution reactions of carbonyl-containing compounds
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The Position
• The carbon next to the carbonyl group is designated as being in the position, hence called the alpha () carbon
• Electrophilic substitution occurs at this position through either an enol or enolate ion
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Alpha Substitution
• Alpha substitution is the substitution (in most cases) of one of the hydrogens attached to the alpha-carbon for an electrophile.
• The reaction occurs through an enol/enolate ion intermediate.
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•Many reaction schemes make use of carbonyl - substitution reactions
•These reactions are one the few general methods for making C-C bonds
• larger molecules can be synthesized from smaller precursors
•Other functional can be introduced into the product molecule
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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 b- hydroxy carbonyl compound
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Keto–Enol Tautomerism
• A carbonyl compound with a hydrogen atom on its carbon rapidly equilibrates with its corresponding enol
• Compounds that differ only by the position of a moveable proton are called tautomers
• Can be catalyzed either by an acid or a base
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•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.
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• Resonance forms are representations of contributors to a single structure
• Tautomers interconvert rapidly while ordinary isomers do not
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Enols
• The enol tautomer is usually present to a very small extent and cannot be isolated
• However, since it is formed rapidly, it can serve as a reaction intermediate
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Acid-Catalyzed Tautomerism
• In acid, a proton is moved from the -carbon by first protonating oxygen and then removing a proton from the carbon.
•Brønsted acids catalyze keto-enol tautomerization by protonating the carbonyl and activating the protons
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Base–Catalyzed Tautomerism
• In the presence of strong bases, ketones and aldehydes act as weak proton donating 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.
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Formation and Stability of Enolate Ions
•The equilibrium mixture contains only a small fraction of the deprotonated, enolate form.
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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.
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The Mechanism of Alpha-Substitution Reactions
• Enols behave as nucleophiles and react with electrophiles because the double bonds are electron-rich compared to alkenes
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General Mechanism of Addition to Enols
• When an enol reacts with an electrophile the intermediate cation readily loses the OH proton to give a substituted carbonyl compound
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Alpha Halogenation of Aldehydes and Ketones • Aldehydes and ketones can be halogenated at their
positions by reaction with Cl2, Br2, or I2 in acidic solution
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• The keto tautomer loses a proton
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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
Evidence for the Rate-Limiting Enol Formation
• The rate of halogenation is independent of the halogen's identity and concentration
• In D3O+ , the H’s are replaced by D’s at the same rate as halogenation
• This is because the barrier to formation of the enol goes through the highest energy transition state in the mechanism
19Rate = k [Ketone][H+]
Elimination Reactions of -Bromoketones
• -Bromo ketones can be dehydrobrominated by base treatment to yield ,b-unsaturated ketones
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Base-Catalyzed 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.
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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.
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O
H
Haloform 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.
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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 Cl2 is used, chloroform is formed; Br2 forms bromoform ; and I2 forms iodoform.
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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
Solution
Alpha Bromination of Carboxylic Acids: The Hell–Volhard–Zelinskii (HVZ) Reaction
• Carboxylic acids do not react with Br2 (unlike aldehydes and ketones)
• They are brominated by a mixture of Br2 and PBr3 (Hell– Volhard–Zelinskii reaction)
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Mechanism of Bromination
• PBr3 converts -COOH to –COBr (Acid halide), which can enolize and add Br2
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Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation • Carbonyl compounds can act as weak acids (pKa of acetone
= 19.3; pKa of ethane = 60)
• The conjugate base of a ketone or aldehyde is an enolate ion - the negative charge is delocalized onto oxygen
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Reagents for Enolate Formation
• Ketones are weaker acids than the OH of alcohols so a more powerful base than an alkoxide is needed to form the enolate
• Sodium hydride (NaH) or lithium diisopropylamide [LiN( i- C3H7)2] are strong enough to form the enolate
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Lithium Diisopropylamide (LDA)
• LDA is from butyllithium (BuLi) and diisopropylamine (pKa 40) • Soluble in organic solvents and effective at low temperature
with many compounds • Not nucleophilic
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b-Dicarbonyls Are More Acidic
• When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced
• Negative charge of enolate ion delocalizes over both carbonyl groups
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Reactivity of Enolate Ions
• The carbon atom of an enolate ion is electron-rich and highly reactive toward electrophiles (enols are not as reactive)
• Reaction on oxygen yields an enol derivative
• Reaction on carbon yields an -substituted carbonyl compound
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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.
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Constraints on Enolate Alkylation
• SN2 reaction:, the leaving group X can be chloride, bromide, iodide, or tosylate
• R should be primary or methyl and preferably should be allylic or benzylic
• Secondary halides react poorly, and tertiary halides don't react at all because of competing elimination
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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.
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The Malonic Ester Synthesis
• For preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain of the substrate ( in most cases, an alkyl halide) by two carbon atoms
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Formation of Enolate and Alkylation
• Malonic ester (diethyl propanedioate) is easily converted into its enolate ion by reaction with sodium ethoxide in ethanol
• The enolate is a good nucleophile that reacts rapidly with an alkyl halide to give an -substituted malonic ester
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Dialkylation
• The product has an acidic -hydrogen, allowing the alkylation process to be repeated
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Hydrolysis and Decarboxylation
• The malonic ester derivative hydrolyzes in acid and loses CO2 (“decarboxylation”) to yield a substituted monoacid
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Decarboxylation of a b-diacid and a b- Ketoacids
• Decarboxylation requires a carbonyl group two atoms away from the CO2H
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Overall Conversion
• The malonic ester synthesis converts an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atoms
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• 1,4-dibromobutane reacts twice, giving a cyclic product
• Three-, four-, five-, and six-membered rings can be prepared in this way
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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–CH2– and CH3CH2–.
Adding these substituents to the enolate of malonic ester eventually gives the correct
product.
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• Show how the malonic ester synthesis is used to prepare cyclohexanecarboxylic acid.
Acetoacetic Ester Synthesis
• Overall: converts an alkyl halide into a methyl ketone
• lengthens the carbon chain of the substrate ( in most cases, an alkyl halide) by three carbon atoms
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Acetoacetic Ester
• carbon is flanked by two carbonyl groups, so it readily becomes an enolate ion
• This can be alkylated by an alkyl halide and also can react with a second alkyl halide
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• Cyclic b-keto esters give 2-substituted cyclohexanones
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Decarboxylation of a b-diacid and a b- Ketoacids
• Decarboxylation requires a carbonyl group two atoms away from the CO2H
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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
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 (Continued) Solution (Continued)
Additional problem II
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• Show how the acetoacetic ester synthesis is used to prepare 1 -cyclopentylethanone.
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Direct Alkylation of Ketones, Esters and Nitriles
• Direct alkylation of monocarbonyl compounds can be carried out in the presence of a strong, sterically hindered base such as LDA in a nonprotic solvent
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Note: Alkylation prefers to occur at the less hindered, more accessible position
Practice I:
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How would prepare each of the following compounds using direct alkylation as the key step:
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