Enols and Enolates 22.1 Introduction to Alpha Carbon Chemistry

4/25/2012

22.1 Introduction to Alpha Carbon 22.1 Introduction to Alpha Carbon Chemistry –Enols and Enolates Chemistry –Enols and Enolates • For carbonyl compounds, Greek letters are often used • The reactions we will explore proceed though either an to describe the proximity of atoms to the carbonyl enol or an enolate intermediate. center.

• This chapter will primarily explore reactions that take place at the alpha carbon.

22.1 Introduction to Alpha Carbon 22.1 Introduction to Alpha Carbon Chemistry –Enols and Enolates Chemistry –Enols and Enolates • Trace amounts of acid or base catalyst provide • In rare cases such as the example below, the enol form equilibriums in which both the enol and keto forms are is favored in equilibrium. present.

• Give two reasons to explain WHY the enol is favored. • How is equilibrium different from resonance?

• At equilibrium, > 99% of the molecules exist in the keto • The solvent can affect the exact percentages. form. WHY?

22.1 Introduction to Alpha Carbon 22.1 Introduction to Alpha Carbon Chemistry –Enols and Enolates Chemistry –Enols and Enolates • Phenol is an example where the enol is vastly favored • The mechanism for the tautomerization depends on over the keto at equilibrium. WHY? whether it is acid catalyzed or base catalyzed.

1 4/25/2012

22.1 Introduction to Alpha Carbon 22.1 Introduction to Alpha Carbon Chemistry –Enols and Enolates Chemistry –Enols and Enolates • The mechanism for the tautomerization depends on • As the tautomerization is practically unavoidable, some whether it is acid catalyzed or base catalyzed. fraction of the molecules will exist in the enol form. • Analyzing the enol form, we see there is a minor (but significant) resonance contributor with a nucleophilic carbon atom.

• Practice with CONCEPTUAL CHECKPOINTs 22.1 through 22.3. Copyright 2012 John Wiley & Sons, Inc. 22-7 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-8 Klein, Organic Chemistry 1e

22.1 Introduction to Alpha Carbon 22.1 Introduction to Alpha Carbon Chemistry –Enols and Enolates Chemistry –Enols and Enolates • In the presence of a strong base, an ENOLATE forms. • The enolate can undergo C‐attack or O‐attack.

• Enolates generally undergo C‐attack. WHY?

• The enolate is much more nucleophilic than in the enol. WHY?

22.1 Introduction to Alpha Carbon 22.1 Introduction to Alpha Carbon Chemistry –Enols and Enolates Chemistry –Enols and Enolates • Alpha protons are the only protons on an aldehyde or • Draw all possible enolates that could form from the ketone that can be removed to form an enolate. following molecule. O

O O • Removing the aldehyde proton, or the beta or gamma proton, will NOT yield a resonance stabilized intermediate. • Practice with SKILLBUILDER 22.1. Copyright 2012 John Wiley & Sons, Inc. 22-11 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-12 Klein, Organic Chemistry 1e

2 4/25/2012

22.1 Introduction to Alpha Carbon 22.1 Introduction to Alpha Carbon Chemistry –Enols and Enolates Chemistry –Enols and Enolates

• Why would a chemist want to form an enolate? • Let’s compare some pKa values for some alpha protons.

• To form an enolate, a base must be used to remove the alpha protons. • The appropriate base depends on how acidic the alpha protons are . • What method do we have to quantify how acidic something is?

22.1 Introduction to Alpha Carbon 22.1 Introduction to Alpha Carbon Chemistry –Enols and Enolates Chemistry –Enols and Enolates • In this case, it is an advantage to have both enolate and aldehyde in solution so they can react with one another.

• When pKa values are similar, both products and reactants are present in significant amounts.

• Show how the electrons might move in the reaction between the enolate and the aldehyde. • Which side will this equilibrium favor?

22.1 Introduction to Alpha Carbon 22.1 Introduction to Alpha Carbon Chemistry –Enols and Enolates Chemistry –Enols and Enolates • If you want the carbonyl to react irreversibly, a stronger • Lithium diisopropylamide (LDA) is an even stronger base base, such as H–, is necessary. that is frequently used to promote irreversible enolate formation.

• When is it synthetically desirable to convert all of the carbonyl into an enolate? • Why is the reaction affectively irreversible?

• LDA features two bulky isopropyl groups. Why would such a bulky base be desirable?

3 4/25/2012

22.1 Introduction to Alpha Carbon 22.1 Introduction to Alpha Carbon Chemistry –Enols and Enolates Chemistry –Enols and Enolates • When a proton is alpha to two different carbonyl • 2,4‐pentanedione is acidic enough that hydroxide or groups, its acidity is increased. alkoxides can deprotonate it irreversibly.

• Draw the resonance contributors that allow • Figure 22.2 summarizes the relevant factors you should 2,4‐pentanedione to be so acidic. consider when choosing a base. • Practice with CONCEPTUAL CHECKPOINTs 22.6 through 22.8. Copyright 2012 John Wiley & Sons, Inc. 22-19 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-20 Klein, Organic Chemistry 1e

22.2 Alpha Halogenation of Enols 22.2 Alpha Halogenation of Enols and Enolates and Enolates

+ • H3O catalyzes the ketoÆenol tautomerism. HOW? • When an unsymmetrical ketone is used, bromination • The enol tautomer can attack a halogen molecule. occurs primarily at the more substituted carbon.

• The major product results from the more stable (more • The process is AUTOCATALYTIC: substituted) enol. – The regenerated acid can catalyze another tautomerization • A mixture of products is generally unavoidable. and halogenation.

22.2 Alpha Halogenation of Enols 22.2 Alpha Halogenation of Enols and Enolates and Enolates • This provides a two‐step synthesis for the synthesis of • The Hell‐Volhard Zelinsky reaction brominates the alpha an α,β‐unsaturated ketone. carbon of a carboxylic acid.

• PBr forms the acyl bromide, which more readily forms • Give a mechanism that shows the role of pyridine. 3 the enol and attacks the bromine. • Other bases, such as potassium tert‐butoxide, can also • Hydrolysis of the acyl bromide is the last step. be used in the second step. • Draw a complete mechanism. • Practice with CONCEPTUAL CHECKPOINTs 22.9 and 22.10. • Practice CONCEPTUAL CHECKPOINTs 22.11 and 22.12. Copyright 2012 John Wiley & Sons, Inc. 22-23 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-24 Klein, Organic Chemistry 1e

4 4/25/2012

22.2 Alpha Halogenation of Enols 22.2 Alpha Halogenation of Enols and Enolates and Enolates • Alpha halogenation can also be achieved under basic • Monosubstitution is not possible. WHY? conditions. • Methyl ketones can be converted to carboxylic acids using excess halogen and hydroxide.

• The formation of the enolate is not favored, but the equilibrium is pushed forward by the second step. • Once all three α protons are substituted, the CBr3 group • Will the presence of the α bromine make the remaining becomes a decent leaving group. α proton more or less acidic?

22.2 Alpha Halogenation of Enols 22.2 Alpha Halogenation of Enols and Enolates and Enolates • Once all three α protons are substituted, the CBr group 3 • The carboxylate produced on the last slide can be becomes a decent leaving group. + protonated with H3O .

• The reaction works well with Cl2, Br2, and I2, and it is known as the haloform reaction. • The last step is practically irreversible. WHY? • The iodoform reaction may be used to test for methyl ketones, because iodoform can be observed as a yellow solid when it forms. • Practice with CONCEPTUAL CHECKPOINTs 22.13 and 22.14.

22.2 Alpha Halogenation of Enols 22.3 Aldol Reactions and Enolates • Give the major product for the reaction below. Be • Recall that when an aldehyde is treated with hydroxide careful of stereochemistry. (or alkoxide), an equilibrium forms where significant amounts of both enolate and aldehyde are present. • If the enolate attacks the aldehyde, an aldol reaction occurs.

• The product features both aldehyde and alcohol groups. • Note the location of the –OH group on the beta carbon.

5 4/25/2012

22.3 Aldol Reactions 22.3 Aldol Reactions

• The aldol mechanism: • The aldol reaction is an equilibrium process that generally favors the products:

• How might the temperature affect the equilibrium?

22.3 Aldol Reactions 22.3 Aldol Reactions

• A similar reaction for a ketone generally does NOT favor • Predict the products for the follow reaction, and give a the β‐hydroxy ketone product. reasonable mechanism. Be careful of stereochemistry.

• Give a reasonable mechanism for the retro‐aldol reaction. • Practice with SKILLBUILDER 22.2.

22.3 Aldol Reactions 22.3 Aldol Reactions

• When an aldol product is heated under acidic or basic • The elimination of water can be promoted under acidic conditions, an α,β‐unsaturated carbonyl forms. or under basic conditions. • Give a reasonable mechanism for each:

• Such a process is called an ALDOL CONDENSATION, because water is given off. • The elimination reaction above is an equilibrium, which generally favors the products. • WHY? Consider enthalpy and entropy.

6 4/25/2012

22.3 Aldol Reactions 22.3 Aldol Reactions • Because the aldol condensation is favored, often it is • When a water is eliminated, two products are possible. impossible to isolate the aldol product without elimination. • Which will likely be the major product? Use the mechanism to explain.

• Condensation is especially favored when extended conjugation results.

22.3 Aldol Reactions 22.3 Aldol Reactions • At low temperatures, condensation is less favored, but the aldol product is still often difficult to isolate in good • Predict the major product of the following reaction. Be yield. careful of stereochemistry. • Practice with SKILLBUILDER 22.3.

22.3 Aldol Reactions 22.3 Aldol Reactions

• Substrates can react in a CROSSED aldol or MIXED aldol • Practical CROSSED aldol reactions can be achieved reaction. Predict the four possible products in the through one of two methods: reaction below. 1. One of the substrates is relatively unhindered and without alpha protons.

• Such a complicated mixture of products is not very synthetically practical. WHY? Copyright 2012 John Wiley & Sons, Inc. 22-41 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-42 Klein, Organic Chemistry 1e

7 4/25/2012

22.3 Aldol Reactions 22.3 Aldol Reactions • Practical CROSSED aldol reactions can be achieved through one of two methods: 1. One of the substrates is relatively unhindered and without alpha protons. 2. One substrate is added dropwise to LDA forming the enolate first. Subsequent addition of the second substrate produces the desired product.

• Practice with SKILLBUILDER 22.4.

22.3 Aldol Reactions 22.3 Aldol Reactions

• Describe a synthesis necessary to yield the following • Cyclic compounds can be formed through compound. intramolecular aldol reactions.

• One group forms an enolate that attacks the other group. • Recall that 5 and 6‐membered rings are most likely to form. WHY? • Practice CONCEPTUAL CHECKPOINTs 22.25 through 22.27. Copyright 2012 John Wiley & Sons, Inc. 22-45 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-46 Klein, Organic Chemistry 1e

22.4 Claisen Condensations 22.4 Claisen Condensations

• Esters also undergo reversible condensations reactions. • Esters also undergo reversible condensations reactions.

• The resulting doubly‐stabilized enolate must be treated • Unlike a ketone or aldehyde, an ester has a leaving with an acid in the last step. WHY? group. • A beta‐ketoester is produced.

8 4/25/2012

22.4 Claisen Condensations 22.4 Claisen Condensations

• There are some limitations to the Claisen condensation: • Crossed Claisen reactions can also be achieved using the 1. The starting ester must have two alpha protons because same strategies employed in crossed aldol reactions. removal of the second proton by the alkoxide ion is what drives the equilibrium forward. 2. Hydroxide cannot be used as the base to promote Claisen condensations because a hydrolysis reaction occurs between hydroxide and the ester. 3. An alkoxide equivalent to the –OR group of the ester is a good base because transesterification is avoided. • Practice CONCEPTUAL CHECKPOINTs 22.28 and 22.29. • Practice with CONCEPTUAL CHECKPOINT 22.30.

22.4 Claisen Condensations 22.4 Claisen Condensations

• Intramolecular Claisen condensations can also be • Give reagents necessary to synthesize the following achieved. molecules.

O • This DIEKMANN CYCLIZATION proceeds through the expected 5‐membered ring transition state. DRAW it.

• Practice with CONCEPTUAL CHECKPOINTs O 22.31 and 22.32. O Copyright 2012 John Wiley & Sons, Inc. 22-51 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-52 Klein, Organic Chemistry 1e

22.5 Alkylation of the Alpha Position 22.5 Alkylation of the Alpha Position

• The alpha position can be alkylated when an enolate is • When 2° or 3° alkyl halides are used, the enolate can act treated with an alkyl halide. as a base in an E2 reaction. SHOW a mechanism. • The aldol reaction also competes with the desired alkylation, so a strong base such as LDA must be used. • Regioselectivity is often an issue when forming enolates. • If the compound below is treated with a strong base, • The enolate attacks the alkyl halide via an SN2 reaction. two enolates can form.

9 4/25/2012

22.5 Alkylation of the Alpha Position 22.5 Alkylation of the Alpha Position • For clarity, the kinetic and thermodynamic pathways are exaggerated below. • Explain the energy differences below using steric and stability arguments.

• What is meant by kinetic and thermodynamic enolate?

22.5 Alkylation of the Alpha Position 22.5 Alkylation of the Alpha Position • LDA is a strong base, and at low temperatures, it will react effectively in an irreversible manner. • Give necessary reagents to synthesize the compound • NaH is not quite as strong, and if heat is available, the below starting with carbon fragments with five carbons system will be reversible. or less. • Practice with CONCEPTUAL CHECKPOINTs 22.33 and 22.24.

22.5 Alkylation of the Alpha Position 22.5 Alkylation of the Alpha Position

• The malonic ester synthesis allows a halide to be • The enolate is treated with the alkyl halide. converted into a carboxylic acid with two additional carbons.

• The resulting diester can be hydrolyzed with acid or • Diethyl malonate is first treated with a base to form a base, and using heat. doubly‐stabilized enolate.

10 4/25/2012

22.5 Alkylation of the Alpha Position 22.5 Alkylation of the Alpha Position

• One of the resulting carboxylic acid groups can be • Here is an example of the overall synthesis. DECARBOXYLATED with heat through a pericyclic reaction.

• Why isn’t the second carboxylic acid group removed?

22.5 Alkylation of the Alpha Position 22.5 Alkylation of the Alpha Position

• Double alkylation can also be achieved: • Give a complete mechanism for the process below.

• Practice with SKILLBUILDER 22.5. • The acetoacetic ester synthesis is a very similar process.

• Practice with SKILLBUILDER 22.6.

22.6 Conjugate Addition Reactions 22.6 Conjugate Addition Reactions

• Recall that α,β‐unsaturated carbonyls can be made • Grignard reagents generally attack the carbonyl position easily through aldol condensations. of α,β‐unsaturated carbonyls yielding a 1,2 addition.

• α,β‐unsaturated carbonyls have three resonance contributors. • In contrast, Gilman reagents generally attacks the beta position giving 1,4 addition, or CONJUGATE ADDITION.

11 4/25/2012

22.6 Conjugate Addition Reactions 22.6 Conjugate Addition Reactions

• Conjugate addition of α,β‐unsaturated carbonyls starts • More reactive nucleophiles (e.g. Grignard) are more with attack at the beta position. likely to attack the carbonyl directly. WHY? • Enolates are generally less reactive than Grignards but more reactive than Gilman reagents, so enolates often give a mixture of 121,2‐ and 141,4‐addit ion products. • • WHY does the Doubly‐stabilized enolates are stable enough to react nucleophile generally primarily at the beta position. favor attacking the beta position?

22.6 Conjugate Addition Reactions 22.6 Conjugate Addition Reactions

• When an enolate attacks a beta carbon, the process is • Give a mechanism showing the reaction between the called a Michael addition. two compounds shown below.

• Practice with CONCEPTUAL CHECKPOINTs 22.44 through 22.46.

22.6 Conjugate Addition Reactions 22.6 Conjugate Addition Reactions

• Because singly‐stabilized enolates do not give high • Enolates and enamines have reactivity in common. yielding Michael additions, Gilbert Stork developed a synthesis using an enamine intermediate. • Recall the enamine synthesis from Chapter 20.

• The enamine is less nucleophilic and more likely to act as a Michael donor.

12 4/25/2012

22.6 Conjugate Addition Reactions 22.6 Conjugate Addition Reactions

• Give reagents necessary to synthesize the molecule below using the Stork enamine synthesis .

O O

• Water hydrolyzes the imine, and tautomerizes • Practice with SKILLBUILDER 22.7. and protonates the enol. Copyright 2012 John Wiley & Sons, Inc. 22-73 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-74 Klein, Organic Chemistry 1e

22.6 Conjugate Addition Reactions 22.7 Synthetic Strategies

• The ROBINSON ANNULATION utilizes a Michael addition • Most of the reactions in this chapter are C–C bond followed by an aldol condensation. forming. • Three of the reactions yield a product with two functional groups. • The positions of the functional groups in the product can be used to design necessary reagents in the synthesis. • Practice with SKILLBUILDER 22.8.

22.7 Synthetic Strategies 22.7 Synthetic Strategies

• Stork enamine synthesis Æ 1,5‐dicarbonyl compounds. • We have learned two methods of alkylation: 1. The alpha position of an enolate attacks an alkyl halide. 2. A Michael donor attacks the beta position of a Michael acceptor. • These two reactions can also be combine d: • Aldol and Claisen Æ 1,3‐difunctional compounds.

• Give a reasonable mechanism. • Practice with SKILLBUILDER 22.9. Copyright 2012 John Wiley & Sons, Inc. 22-77 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-78 Klein, Organic Chemistry 1e

13 4/25/2012

22.7 Synthetic Strategies

• Give reagents necessary for the following synthesis. O O