Chapter 22:Chapter 22:Carbonyl Carbonyl αααααααα--SubstitutionsSubstitutionsCarbonyl Carbonyl αααααααα--SubstitutionsSubstitutions

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� So far, all the reactions of carbonyl compounds that we have seen were directly at the carbonyl.

� But there is another possibility if the carbonyl has αααα-hydrogens, αααα−−−−substitutionαααα-hydrogens, αααα−−−−substitution

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� Keto-Enol Tautomerism (22-2)This substitution reaction can take place under acidic condition from the enol tautomer acting as the nucleophile.

Or under basic condition.Or under basic condition.

Tautomerism: Rapid conversion of two isomeric chemical species

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� Under weakly basic (RO- or HO-) conditions, only a small amount of the enolate anion can be produced. In these cases the nucleophile in the substitution reaction is most likely the enol tautomer.

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� However, the use of stronger bases such as LDA(Lithium DiisopropylAmide) generates the enolate ion in quantitative amount, making this species the nucleophile in the substitution reaction.

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Practice QuestionsPractice Questions� Draw the enol tautomers for each of the following compounds. For compounds that have more than one enol tautomer, indicate which is more stable.O

O

O

O331

• Alkylation of Enolate Ion (22-3)

The reaction follows a SN2 mechanism where the nucleophile is the enolate anion. Alkylation of enolate anion is normally at the carbon, but some side reaction at the oxygen is also possible.

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333

� This reaction has some serious limitations:◦ Difficult at best with ketones, esters and nitriles◦ Carbonyl with only one type of αααα-proton give good results◦ Only a strong base such as LDA can be used◦ Condensation is often a side reaction.◦ Cannot be done with aldehydes.◦ To be successful, it requires small reactive alkyl ◦ To be successful, it requires small reactive alkyl halides (R-X)� reactivity order: allylic > benzylic > methyl > 1o

◦ In practice, alkylation of enolate is rarely attempted

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� The main reason for all of these limitations is because similar conditions are used to carry out condensation reactions. Alkylation and condensation always compete with one another.

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� In order to minimize this problem, one must form the enolate ion quantitatively and rapidly. The use of LDA is recommended (yet condensation will still take place).

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• Formation and Alkylation of Enamines (22-4)This is a milder alternative to direct alkylation of carbonyl and is the best way to alkylate aldehydes. Aldehydes cannot be alkylated directly but using an enamine, followed by an hydrolysis, alkylated aldehydes can be obtained. Ketones can also be obtained via this method.aldehydes can be obtained. Ketones can also be obtained via this method.

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� Enamines are very similar to enolate ions in their structures…and reactivity.

� In the presence of an electrophile, they will act as the nucleophile and produce the iminium ion. as the nucleophile and produce the iminium ion. This ion will generate the corresponding carbonyl (ketone or aldehyde) on hydrolysis.

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� The synthesis of the enamine follows a similar mechanism as the formation of the imine (Chapter 18). However, here the carbinolamine cannot eliminate a proton from the amine function and the elimination takes place at the αααα position instead.

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� Acylation of enamines is also easy to do by an acyl substitution mechanism with acid chlorides, ββββ diketones are obtained.

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Practice QuestionsPractice Questions� How would you prepare the following compound using an enamine intermediate?

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� How would you prepare the following compounds from a ketone and an alkyl halide?

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• αααα-Halogenation of Ketones (22-5)This reaction if possible for any halogens (Cl2, Br2, I2) under acidic conditions (acetic acid is often used). Therefore, the mechanism will proceed via the enol intermediate.

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� Under basic conditions it also possible carry out this reaction. However, if more than one αααα-hydrogens are present, they will all be substituted.

O

H

ClCl2

OH , H2O_

O

Cl

ClO

Cl

ClCl

O

Cl

ClClCl

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� This polyhalogenation under basic conditions is the basis of the haloform reaction producing carboxylic acid. Because the CX3 group on the carbonyl is a good leaving group, acyl substitution with the hydroxide ion takes place leading to the formation of carboxylate anions.

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• αααα Bromination of Acids: The HVZ Reaction (22-6)

The HVZ (Hell-Volhard-Zelinsky) reaction is not one carried out on aldehydes/ketones but rather is a reaction of a carboxylic acid, and is very similar to the halogenation reaction we just covered. This reaction gives αααα-brominated carboxylic acids.gives αααα-brominated carboxylic acids.

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� Because acids, esters and amides do not enolize enough, they cannot be brominated directly. Hence, the acid is transformed first into the acid bromide, αααα-brominated and hydrolyzed back to a carboxylic acid.

� The mechanism is shown on the next slide. � The mechanism is shown on the next slide. The formation of the intermediate acid bromide (labelled A on the next slide) follow the same mechanism we have seen for alcohols (Chapter 11 Alcohols/phenols)

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Mechanism of the HVZ ReactionMechanism of the HVZ Reaction

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A

• The Aldol Condensation (22-7)In the aldol condensation, the same carbonyl can be used as the nucleophile (enolate) and as the electrophile (carbonyl). The result is the formation of a ββββ-hydroxycarbonyl. This is the reason why alkylation was so difficult to perform, this reaction always competes with others whenever an enolate anion is produced.

R CH3

O

R CH2-

Oenolate ketone

nucleophile electrophile

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� Ketones and aldehydes will give aldol condensation.

H

O

H

O

OH- H

O

OH

12

3

12

3

123

12

3

O O

O O

OH-

O

OH

123 1

23

12312

3

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Based Catalyzed Aldol Based Catalyzed Aldol AdditionAddition

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Practice QuestionPractice Question� What is the aldol addition products are formed from the following carbonyls?

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� The aldol condensation of aldehydes and ketones can also be catalyzed by acid. The enol tautomer is acting as the nucleophile in these cases.

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� Dehydration of the Aldol Product (22-8)◦ Aldol products, ββββ-hydroxycarbonyls are very easy to dehydrate because the resulting product is very stable (unsaturated carbonyls). Since the aldol addition is at equilibrium, this step is usually necessary to complete the reaction. These two steps together (aldol addition + dehydration) will reaction. These two steps together (aldol addition + dehydration) will generate αααα,ββββ-unsaturated carbonyl.

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� The dehydration of the aldol addition product can be done under acidic or basic conditions.

O

H2SO4

O

H

O NaOHH

O

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BaseBase--Catalyzed Dehydration of Aldol Catalyzed Dehydration of Aldol ProductProduct

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AcidAcid--Catalyzed Dehydration of Aldol Catalyzed Dehydration of Aldol ProductProduct

H

O B-

H

O OH

H+

H

OH OH

H

OH OH+

H+

H

B-

H

OH OH

H+

H

OH OH2

+

H

OH +

B-

H

O

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Competition Between Competition Between Condensation and Condensation and αααααααα--Substitution.Substitution.� We have seen that for both of these reactions an enolate anion must be formed. Different conditions can be used to control the reaction outcome depending on the type of reaction needed:

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• Crossed Aldol Condensations (22-9)� The condensation reaction between two structurally different aldehydes/ketones.

� For example, what would be the product of this reaction? How many products can be formed?be formed?

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� These mixed aldol (cross aldol) reactions are very difficult to control and more than one product is usually obtained.

� However, it is possible to limit the possibilities by choosing the correct reaction conditions:A- One carbonyl has no αααα-hydrogen (cannot enolize)B- Form the enolate first, then add the second carbonyl

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A- One carbonyl has no αααα-hydrogen (cannot enolize)

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B- Form the enolate first, then add the second carbonyl

O

LDA

O-

f i f h l

H

O1)

2) H2O

O OH

formation of the enolateshould be quantitative

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Practice QuestionPractice Question� What are the products of the following crossed aldol additions?

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• Aldol Cyclizations (22-10)

When a molecule contains two carbonyl groups within its structure, it is possible for this molecule to cyclize via an aldol addition. The stability of cyclic structures is important, hence 5 and 6-membered rings are favoured.rings are favoured.

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Practice QuestionPractice Question� What is the major product of the following reactions?

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� Planning Syntheses using Aldol Condensations(22-11)When planning to carry out a synthesis that will involved an aldol condensation, always look at the bond between the αααα and ββββ carbons since this is the bond created during the aldol condensation.

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• Claisen Condensation (22-12)

This reaction is identical to the aldol condensation but takes place between 2 esters. A small difference exists in the mechanism to explain the formation of the final product, a ββββ-ketoester. You should recognize in the second step the acyl substitution mechanism that we have seen in a substitution mechanism that we have seen in a previous chapter.

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� In this reaction a second step (acidic workup) is necessary since the product of the claisen condensation is more acidic than the original esters and is deprotonated with the base that is expelled.

R CH2 CO

C RCO

R'O-

H3O+

R CH2 CO

CH

RCO

R'O

pKa~ 11

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� The Dieckmann Condensation (22-13)This is similar to the intramolecular Aldol reaction, 5 and 6-membered rings are preferred.

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• Crossed Claisen Condensation (22-14)

Similar to the Aldol condensation, when two different esters are used, cross condensation results.

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� Other carbonyl can be used to replace one of the ester. When a ketone is used, it always forms the enolate since the protons are more acidic. Reaction with an ester gives a ββββ-diketone.

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� Reaction of a ketone with diethyl carbonate is another good method to get ββββ-ketoesters.

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Practice QuestionsPractice Questions� Which of the following cannot give Claisen condensation?

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� What are the products of the following reactions?

O

OCH3

O1) CH3O

-

2) HCl

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• Malonic ester synthesis (22-16)In this reaction the αααα-hydrogen are very acidic because they are located between 2 carbonyl groups…hence, we say that the carbonyl is activated. The deprotonation is quantitative and unambiguous. Carboxylic acids are obtained after an hydrolysis and decarboxylation steps.decarboxylation steps.

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� Simple bases are used because of the increased acidity of the ββββ-dicarbonyl compounds.

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Examples of the Examples of the MalonicMalonic Ester SynthesisEster Synthesis

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� We have seen how to hydrolyze (undeer basic or acidic conditions) esters to acids (section on carboxylic acid derivatives) . Because of the structure of this diacid, it is very easy (just requires heat) to remove CO2 and obtain the product, a carboxylic acid.acid.

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Practice QuestionPractice Question� What are the products of the following reactions?

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• Acetoacetic ester synthesis (22-17)The principles seen in the malonic ester synthesis also apply here…except, because there is only one possible carboxyl group to eliminate, a ketone will be obtained. This is an excellent method to get an alkylated ketone and avoid condensation. This reaction will work for any ββββ-ketoester.ketone and avoid condensation. This reaction will work for any ββββ-ketoester.

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� Decarboxylation follows the same mechanism, but only one carboxyl group is present, hence a ketone is produced.

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Example of Example of AcetoaceticAcetoacetic Ester SynthesisEster Synthesis

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Practice QuestionsPractice Questions� What alkyl bromide would do you need in the malonic ester synthesis of the following acids?

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� What alkyl bromide would you use to carry out the acetoacetic ester synthesis of the following ketones?

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• Michael Addition (22-18)

Enolate ion are not as nucleophilic as other ion such as RLi or RMgX. This is due to the resonance stabilization. Because of this, enolate ion will add in a conjugate fashion in the presence of αααα,ββββ-unsaturatedcarbonyl. This reaction is called the carbonyl. This reaction is called the Michael Addition.

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� The Michael addition will work with any enolate ion, but the results are better with a stable enolate is used. Enolates from:◦ ββββ-ketoesters

◦ ββββ-diketones◦ ββββ-diketones

◦ Malonic ester

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� Normally the reactant forming the enolate is called: Michael Donor (because it provides the electrons for the new C-C bond)

� The reactant that is attacked, the αααα,ββββ-� The reactant that is attacked, the αααα,ββββ-unsaturated compound is called the Michael Acceptor (because it accepts the electron pair).

� These reactants are not limited to carbonyl compounds (see next slide)

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Mechanism of the Michael Mechanism of the Michael AdditionAddition

Example of Michael AdditionExample of Michael AdditionExample of Michael AdditionExample of Michael Addition

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Practice QuestionPractice Question� How would you prepare the following compound using a Michael addition in your synthesis?

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• Robinson Annulation (18.17)qAnnulation: Formation of a ring structure from acyclic structure.

qThe Robinson Annulation is a two step process.q(1) Michael Additionq(2) Intramolecular Aldol Condensationq(2) Intramolecular Aldol Condensation

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Mechanism of Robinson AnnulationMechanism of Robinson Annulation

393

� How would you prepare the following compound using a Robinson Annulation?

� The key questions are, which part of this molecule came from the Michael donor, which one came from the Michael acceptor?

394

� First identify the ββββ and γγγγ carbon on the target molecule…count going away from the double bond.

� Draw a line going through the ββββ and γ γ γ γ carbon and splitting the double bond in half O

acceptor

donor395

� Therefore, in order to carry out this synthesis, we need:

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Practice QuestionsPractice Questions� Propose a synthesis for the following compound, using a Robinson Annulation?

397

� What are the product of the following Robinson Annulations?

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