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. Copyright 2012 John Wiley & Sons, Inc. 22-1 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-2 Klein, Organic Chemistry 1e 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? Copyright 2012 John Wiley & Sons, Inc. 22-3 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-4 Klein, Organic Chemistry 1e 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. Copyright 2012 John Wiley & Sons, Inc. 22-5 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-6 Klein, Organic Chemistry 1e 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? Copyright 2012 John Wiley & Sons, Inc. 22-9 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-10 Klein, Organic Chemistry 1e 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? Copyright 2012 John Wiley & Sons, Inc. 22-13 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-14 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 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? Copyright 2012 John Wiley & Sons, Inc. 22-15 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-16 Klein, Organic Chemistry 1e 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? Copyright 2012 John Wiley & Sons, Inc. 22-17 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-18 Klein, Organic Chemistry 1e 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. Copyright 2012 John Wiley & Sons, Inc. 22-21 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-22 Klein, Organic Chemistry 1e 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? Copyright 2012 John Wiley & Sons, Inc. 22-25 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-26 Klein, Organic Chemistry 1e 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. Copyright 2012 John Wiley & Sons, Inc. 22-27 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-28 Klein, Organic Chemistry 1e 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. Copyright 2012 John Wiley & Sons, Inc. 22-29 Klein, Organic Chemistry 1e Copyright 2012 John Wiley & Sons, Inc. 22-30 Klein, Organic Chemistry 1e 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? Copyright 2012 John Wiley & Sons, Inc.