Alpha Carbon Chemistry: Enols and Enolates Chapter 22 Alpha Carbon Chemistry: Enols and Enolates Suggested Problems –

Introduction Alpha Carbon Chemistry: Enols and Enolates For carbonyl compounds, Greek letters are often used to describe the proximity of atoms to the carbonyl center This chapter will primarily explore reactions that take place at the alpha carbon

Introduction Alpha Carbon Chemistry: Enols and Enolates The reactions we will explore proceed though either an enol or an enolate intermediate

Introduction Alpha Carbon Chemistry: Enols and Enolates Trace amounts of acid or base catalyst provide equilibriums in which both the enol and keto forms are present How is equilibrium different from resonance? At equilibrium, >99% of the molecules exist in the keto form. These are tautomers. Resonance structures do not differ in the arrangement of their atoms.

Introduction Alpha Carbon Chemistry: Enols and Enolates In rare cases such as the example below, the enol form is favored in equilibrium Give two reasons to explain WHY the enol is favored The solvent can affect the exact percentages Intramolecular H bonding and conjugation.

Introduction Alpha Carbon Chemistry: Enols and Enolates Phenol is an example where the enol is vastly favored over the keto at equilibrium. WHY?

Introduction Alpha Carbon Chemistry: Enols and Enolates The mechanism for the tautomerization depends on whether it is acid catalyzed or base catalyzed

Introduction Alpha Carbon Chemistry: Enols and Enolates The mechanism for the tautomerization depends on whether it is acid catalyzed or base catalyzed The difference between acid and base catalysis is merely the order of events: protonation and deprotonation

Introduction Alpha Carbon Chemistry: Enols and Enolates As the tautomerization is practically unavoidable, some 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

Introduction Alpha Carbon Chemistry: Enols and Enolates In the presence of a strong base, an enolate forms The enolate is much more nucleophilic than the enol. WHY?

Introduction Alpha Carbon Chemistry: Enols and Enolates The enolate can undergo C-attack or O-attack Enolates generally undergo C-attack. WHY?

Introduction Alpha Carbon Chemistry: Enols and Enolates Alpha protons are the only protons on an aldehyde or ketone that can be removed to form an enolate Removing the aldehyde proton or the beta or gamma proton will NOT yield a resonance stabilized intermediate Practice with SkillBuilder 22.1

Introduction Alpha Carbon Chemistry: Enols and Enolates Draw all possible enolates that could form from the following molecule

Introduction Alpha Carbon Chemistry: Enols and Enolates Why would a chemist want to form an enolate? 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?

Introduction Alpha Carbon Chemistry: Enols and Enolates Let’s compare some pKa values for some alpha protons A base from an acid with a pKa higher than 18-20 will pull the alpha proton in these molecules.

Introduction Alpha Carbon Chemistry: Enols and Enolates When pKa values are similar, both products and reactants are present in significant amounts Which side will this equilibrium favor?

Introduction Alpha Carbon Chemistry: Enols and Enolates In this case, it is a disadvantage to have both enolate and aldehyde in solution at the same time as they can react with one another Show how the electrons might move in the reaction between the enolate and the aldehyde

Introduction Alpha Carbon Chemistry: Enols and Enolates If you want the carbonyl to generate the enolate irreversibly, a stronger base such as H- is necessary By converting the aldehyde completely to the enolate, it is less likely to react with itself. It can then be employed in a reaction with another nucleophile.

Introduction Alpha Carbon Chemistry: Enols and Enolates LDA is an even stronger base that is frequently used to promote irreversible enolate formation Why is the reaction effectively irreversible? LDA features two bulky isopropyl groups. Why would such a bulky base be desirable?

Introduction Alpha Carbon Chemistry: Enols and Enolates When a proton is alpha to two different carbonyl groups, its acidity is increased Draw the resonance contributors that allow 2,4-pentanedione to be so acidic

Introduction Alpha Carbon Chemistry: Enols and Enolates When a proton is alpha to two different carbonyl groups, its acidity is increased Draw the resonance contributors that allow 2,4-pentanedione to be so acidic

Introduction Alpha Carbon Chemistry: Enols and Enolates 2,4-pentanedione is acidic enough that hydroxide or alkoxides can deprotonate it irreversibly Figure 22.2 summarizes the relevant factors you should consider when choosing a base Practice with conceptual checkpoints 22.6 through 22.8

Introduction Alpha Carbon Chemistry: Enols and Enolates Practice with conceptual checkpoints 22.6 through 22.8

Alpha Halogenation of Enols and Enolates H3O+ catalyzes the ketoenol tautomerism. HOW? The enol tautomer can attack a halogen molecule The process is autocatalytic –the regenerated acid can catalyze another tautomerization and halogenation

Alpha Halogenation of Enols and Enolates When an unsymmetrical ketone is used, bromination occurs primarily at the more substituted carbon The major product results from the more stable (more substituted) enol A mixture of products is generally unavoidable

Alpha Halogenation of Enols and Enolates This provides a two step synthesis for the synthesis of an α,β-unsaturated ketone Give a mechanism that shows the role of pyridine Other bases such as potassium tert-butoxide can also be used in the second step Practice with conceptual checkpoints 22.9 and 22.10

Alpha Halogenation of Enols and Enolates Give a mechanism that shows the role of pyridine

Alpha Halogenation of Enols and Enolates The Hell-Volhard Zelinski reaction brominates the alpha carbon of a carboxylic acid PBr3 forms the acyl bromide, which more readily forms the enol and attacks the bromine Hydrolysis of the acyl bromide is the last step Draw a complete mechanism Practice checkpoints 22.11 and 22.12

Alpha Halogenation of Enols and Enolates Carboxylic acids, esters, and amides do not readily convert to their corresponding enols. However, if the acid is converted to an acid bromide first, the enol can form.

Alpha Halogenation of Enols and Enolates Alpha halogenation can also be achieved under basic conditions The formation of the enolate is not favored, but the equilibrium is pushed forward by the second step Will the presence of the α bromine make the remaining α proton more or less acidic?

Alpha Halogenation of Enols and Enolates Monosubstitution is not possible. WHY? Methyl ketones can be converted to carboxylic acids using excess halogen and hydroxide Once all three α protons are substituted, the CBr3 group becomes a decent leaving group The monosubstituted product is more acidic and undergoes enol formation again.

Alpha Halogenation of Enols and Enolates Once all three α protons are substituted, the CBr3 group becomes a decent leaving group The last step is practically irreversible. WHY?

Alpha Halogenation of Enols and Enolates The carboxylate produced on the last slide can be protonated with H3O+ The reaction works well with Cl2, Br2, and I2, and it is known as the haloform reaction The iodoform reaction may be used to test for methyl ketones, because iodoform can be observed as a yellow solid when it forms The haloform reaction is most efficient when the other side of the ketone has no a protons Practice with conceptual checkpoints 22.13 and 22.14

Alpha Halogenation of Enols and Enolates Give the major product for the reaction below. Be careful of stereochemistry

Aldol Reactions When an aldehyde is treated with hydroxide (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 C – A b-hydroxy aldehyde is obtained

Aldol Reactions The aldol mechanism

Aldol Reactions The aldol reaction is an equilibrium process that generally favors the products How might the temperature affect the equilibrium? Could a dehydration drive the equilibrium to form product?

Aldol Reactions A similar reaction for a ketone generally does NOT favor the β-hydroxy ketone product Give a reasonable mechanism for the retro-aldol reaction Practice with SkillBuilder 22.2

Aldol Reactions Give a reasonable mechanism for the retro-aldol reaction

Aldol Reactions Predict the products for the follow reaction, and give a reasonable mechanism. Be careful of stereochemistry

Aldol Reactions Predict the products for the follow reaction, and give a reasonable mechanism. Be careful of stereochemistry Because of the basic conditions, each stereocenter at an alpha carbon will be racemized

Aldol Reactions When an aldol product is heated under acidic or basic conditions, an α,β-unsaturated carbonyl forms 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

Aldol Reactions The elimination of water can be promoted under acidic or under basic conditions Give a reasonable mechanism for each

Aldol Reactions Give a reasonable mechanism for each Base promoted Acid promoted

Aldol Reactions When a water is eliminated, two products are possible Which will likely be the major product? Use the mechanism to explain

Aldol Reactions Because the aldol condensation is favored, often it is impossible to isolate the aldol product without elimination Condensation is especially favored when extended conjugation results

Aldol Reactions At low temperatures, condensation is less favored, but the aldol product is still often difficult to isolate in good yield Practice with SkillBuilder 22.3

Aldol Reactions Predict the major product of the following reaction. Be careful of stereochemistry Because of the basic conditions, each stereocenter at an alpha carbon will be racemized

Aldol Reactions Substrates can react in a crossed aldol or mixed aldol reaction. Predict the 4 possible products in the reaction below Such a complicated mixture of products is not very synthetically practical.

Aldol Reactions Practical crossed aldol reactions can be achieved through one of two methods One of the substrates is relatively unhindered and without alpha protons

Aldol Reactions One of the substrates is relatively unhindered and without alpha protons

Aldol Reactions Practical crossed aldol reactions can be achieved through one of two methods 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

Aldol Reactions Describe a synthesis necessary to yield the following compound

Aldol Reactions Describe a synthesis necessary to yield the following compound

Aldol Reactions Cyclic compounds can be formed through 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

Claisen Condensations Esters also undergo reversible condensations reactions Unlike a ketone or aldehyde, an ester has a leaving group

Claisen Condensations Esters also undergo reversible condensations reactions The resulting doubly-stabilized enolate must be treated with an acid in a last step. WHY? A beta-keto ester is produced

Claisen Condensations There are some limitations to the Claisen condensation The starting ester must have 2 alpha protons, because removal of the second proton by the alkoxide ion is what drives the equilibrium forward Hydroxide cannot be used as the base to promote Claisen condensations, because a hydrolysis reaction occurs between hydroxide and the ester 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

Claisen Condensations Crossed Claisen reactions can also be achieved using the same strategies employed in crossed aldol reactions Practice with conceptual checkpoint 22.30 In the first example, there are no alpha protons on the one ester so an enolate will not be generated from it to interfere. In the second example, LDA converts all of the aldehyde into the enolate before the second ester is added.

Claisen Condensations Intramolecular Claisen condensations can also be achieved This Diekmann cyclization proceeds through the expected 5-membered ring transition state. DRAW it Practice with conceptual checkpoints 22.31 and 22.32

Claisen Condensations Give reagents necessary to synthesize the following molecules

Claisen Condensations Give reagents necessary to synthesize the following molecules

Alkylation of the Alpha Proton The alpha position can be alkylated when an enolate is treated with an alkyl halide The enolate attacks the alkyl halide via an SN2 reaction

Alkylation of the Alpha Proton When 2° or 3° alkyl halides are used, the enolate can act as a base in an E2 reaction. The aldol reaction can compete 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, two enolates can form – see next few slides

Alkylation of the Alpha Proton What is meant by kinetic and thermodynamic enolate? See next few slides for details

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

Alkylation of the Alpha Proton LDA is a strong base, and at low temperatures, it will react effectively in an irreversible manner NaH is not quite as strong, and if heat is available, the system will be reversible Practice with conceptual checkpoints 22.33 and 22.24

Alkylation of the Alpha Proton Give necessary reagents to synthesize the compound below starting with carbon fragments with 5 carbons or less

Alkylation of the Alpha Proton The malonic ester synthesis allows a halide to be converted into a carboxylic acid with two additional carbons Diethyl malonate is first treated with a base to form a doubly-stabilized enolate

Alkylation of the Alpha Proton The enolate is treated with the alkyl halide The resulting diester can be hydrolyzed with acid or base using heat

Alkylation of the Alpha Proton One of the resulting carboxylic acid groups can be decarboxylated with heat through a pericyclic reaction Why isn’t the second carboxylic acid group removed?

Alkylation of the Alpha Proton Here is an example of the overall synthesis

Alkylation of the Alpha Proton Double alkylation can also be achieved The acetoacetic ester synthesis is a very similar process Practice with SkillBuilder 22.5

Alkylation of the Alpha Proton Give a complete mechanism for the process below Practice with SkillBuilder 22.6

Alkylation of the Alpha Proton Give a complete mechanism for the process below

Conjugate Addition Reactions Recall that α,β-unsaturated carbonyls can be made easily through aldol condensations α,β-unsaturated carbonyls have three resonance contributors Which contributors are electrophilic?

Conjugate Addition Reactions Grignard reagents generally attack the carbonyl position of α,β-unsaturated carbonyls yielding a 1,2 addition In contrast, Gilman reagents generally attacks the beta position giving 1,4 addition or conjugate addition

Conjugate Addition Reactions Conjugate addition of α,β-unsaturated carbonyls starts with attack at the beta position WHY is the nucleophile generally favored to attack the beta position?

Conjugate Addition Reactions More reactive nucleophiles (e.g., Grignard) are more 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 1,2- and 1,4- addition products Doubly-stabilized enolates are stable enough to react primarily at the beta position

Conjugate Addition Reactions When an enolate attacks a beta carbon, the process is called a Michael addition

Conjugate Addition Reactions Give a mechanism showing the reaction between the two compounds shown below Practice with conceptual checkpoints 22.44 through 22.46

Conjugate Addition Reactions Because singly-stabilized enolates do not give high yielding Michael additions, Gilbert Stork developed a synthesis using an enamine intermediate Recall the enamine synthesis from chapter 20

Conjugate Addition Reactions Enolates and enamines have reactivity in common The enamine is less nucleophilic and more likely to act as a Michael donor

Conjugate Addition Reactions Water hydrolyzes the imine and tautomerizes and protonates the enol

Conjugate Addition Reactions Give reagents necessary to synthesize the molecule below using the Stork enamine synthesis Practice with SkillBuilder 22.7

Conjugate Addition Reactions Give reagents necessary to synthesize the molecule below using the Stork enamine synthesis

Conjugate Addition Reactions The Robinson Annulation utilizes the a Michael addition followed by an aldol condensation Practice checkpoints 22.49 and 22.50

Synthetic Strategies Most of the reactions in this chapter are C-C bond 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 – see next few slides Practice with SkillBuilder 22.8

Synthetic Strategies Stork enamine synthesis  1,5-dicarbonyl compounds Aldol and Claisen  1,3-difunctional compounds

Synthetic Strategies We have learned two methods of alkylation The alpha position of an enolate attacks an alkyl halide A Michael donor attacks the beta position of a Michael acceptor These two reactions can also be combined Give a reasonable mechanism Practice with SkillBuilder 22.9

Synthetic Strategies Give a reasonable mechanism

Synthetic Strategies Give reagents necessary for the following synthesis

Synthetic Strategies Give reagents necessary for the following synthesis

Additional Practice Problems Explain why an enolate is more likely to produce products resulting from attack by the alpha carbon than direct attack by the oxygen. Is the argument kinetic or thermodynamic or both? Kinetically, an enolate might be expected to attack from the oxygen, because the oxygen can stabilize the partial negative charge that is present during the transition state. On the other hand, a double bond is also present during the transition state, and the C=O double bond is more stable than the C=C double bond. The more stable C=O during that transition state stabilizes attack from the alpha carbon position. However, it is thermodynamics that generally determines the products, because these reactions are often readily reversible, the C=O stability in one product favors its formation once equilibrium is reached.

Additional Practice Problems Give the major products for the reaction below

Additional Practice Problems Using both kinetic and thermodynamic arguments, explain why aldol reactions involving a ketone are less product favored than those involving aldehydes. Kinetic: When acting as an electrophile colliding with enolates, ketones are BOTH more sterically hindered, so they form higher energy transition states AND have less of a partial positive charge (due to hyperconjugation and induction), so they are lower in energy and have higher Eact. Also, the enolate that forms from a ketone has a C=C in its major resonance contributor that is more stabile bc it is more substituted with carbons making it lower in energy and giving it a higher Eact. Thermodynamic: Sterics is the main reason why the product of an aldol reaction with a ketone is less stable shifting the reaction to the reactants in the equilibrium.

Additional Practice Problems Give reagents necessary to produce the product below using aldol chemistry. NaOH is chosen because it promotes the thermodynamic enolate formation Elimination cannot occur after the reaction, because there is no alpha proton to remove

Additional Practice Problems Give reagents necessary for the synthesis below In step 5, a mixture of products may form due to competition between the kinetic and thermodynamic enolates

Additional Practice Problems Give reagents necessary for the synthesis below