Objectives for Chapter 23 Draw the mechanism and predict the products for an aldol addition and condensation reaction Explain the use of LDA versus NaOH and the reversibility of the enolate formation Predict and understand the preferences for product formation with mixed aldol reactions Explain how to circumvent these preferences experimentally Draw the mechanism and predict the products for a Claisen condensation (and the intramolecular ester condensation called the Dieckmann) Explain why the reaction does not give product without a final deprotonation step Draw the mechanism and predict the products for a Michael addition, a Stork reaction, and the Robinson annulation Predict the reactants necessary to synthesize a desired product using the above reactions = retrosynthesis! A. Rosan Chem 350

23.1 Aldol addition reaction ChemAct 26A: CTQ #1 23.1 Aldol addition reaction Q: What two functional groups are in the product Q: Why is the above reaction called the aldol reaction? Q: How many starting organic molecules do you need to make one molecule of product? Q: Which bond is the new C-C bond formed between the two aldehydes? (CQ) A. Rosan Chem 350

Which bond is the new C-C bond formed between the two aldehydes? 23.1 The aldol reaction Which bond is the new C-C bond formed between the two aldehydes? A B C D I’m not sure A. Rosan Chem 350

23.1 Aldol addition reaction ChemAct 26A: CTQ #1 23.1 Aldol addition reaction Q: Why is the above reaction called the aldol reaction? Q: Which bond is the new C-C bond formed between the two aldehydes? Q: Is there a structural difference between the two aldehydes? Q: Is the blue propanal a nucleophile or an electrophile? Is the red propanal a nucleophile or an electrophile? Draw the reaction mechanism to support your hypothesis. A. Rosan Chem 350

23.1 The aldol reaction For the following reaction, how many different aldol products might you form? (mechanism?) 1 2 3 4 I’m not sure A. Rosan Chem 350

23.1 Aldol addition reaction Example. Draw the mechanism and predict the product/s. A. Rosan Chem 350

23.1 Aldol reaction Retrosynthetic analysis Example. How would I synthesize the following molecule? Which synthon would be my nucleophile? Which synthon would be my Electrophile? (What are my two choices?) A. Rosan Chem 350

23.1 Aldol reaction ChemActivity 26A Read Model 2 and answer CTQs # 2 - 6 on page 460. Regarding CTQ #6, the same reason applies for each aldehyde. A. Rosan Chem 350

Aldol is a process not a name ! For many reasons, the aldol reaction can be annoying and complicated. Let’s discuss them! A. Rosan Chem 350

With NaOH, is the enolate anion formation reversible or irreversible? 23.2 Carbonyl condensations v ersus alpha substitution With NaOH, is the enolate anion formation reversible or irreversible? Reversible Irreversible I’m not sure A. Rosan Chem 350

With LDA, is the enolate anion formation reversible or irreversible? 23.2 Carbonyl condensations versus alpha substitution With LDA, is the enolate anion formation reversible or irreversible? Reversible Irreversible I’m not sure A. Rosan Chem 350

With these given conditions, can the aldol product form? 23.2 Carbonyl condensations versus alpha substitution With these given conditions, can the aldol product form? Yes No I’m not sure A. Rosan Chem 350

With these given conditions, can the aldol product form? 23.2 Carbonyl condensations versus alpha substitution With these given conditions, can the aldol product form? Formation of enolate anion is irreversible and immediate – no electrophilic acetaldehyde will be available to be attacked. Yes No I’m not sure A. Rosan Chem 350

Aldol issues Be careful with the reagents that you use! LDA irreversibly forms the enolate – do you have enough electrophile left? A. Rosan Chem 350

23.5 Mixed aldol reactions How many potential products could be generated from the following two aldehydes? (Draw the products out) One Two Three Four I’m not sure A. Rosan Chem 350

23.5 Mixed aldol reactions Chem Act 26A, CTQ # 10, page 461 Draw Them Q: How many potential products could be generated from the following two aldehydes? A. Rosan Chem 350

Aldol issues Be careful with the reagents that you use! LDA irreversibly forms the enolate – do you have enough electrophile left? Expect mixed aldol products, unless you’ve taken the proper precautions! Separation can be tedious! A. Rosan Chem 350

23.5 Mixed aldol reactions Q: How many potential products could be generated from the following two aldehydes? Q: How can you avoid mixed aldol products? Choose one compound without α-H’s. Choose one compound with very acidic α-H’s. A. Rosan Chem 350

In your opinion, which is the better electrophile? (Why?) 23.5 Mixed aldol reactions In your opinion, which is the better electrophile? (Why?) Benzaldehyde Acetaldehyde I’m not sure ChemAct 26B: Model 5 (page 464) A. Rosan Chem 350

Based on your previous answer, which product is favored? A or B 23.5 Mixed aldol reactions Based on your previous answer, which product is favored? A or B A B I’m not sure ChemAct 26B: Model 5 (page 464) A. Rosan Chem 350

Aldol issues Be careful with the reagents that you use! LDA irreversibly forms the enolate – do you have enough electrophile left? Expect mixed aldol products, unless you’ve taken the proper precautions! Steric effects are a factor when deciding the better electrophile! A. Rosan Chem 350

23.5 Mixed aldol reactions ChemActivity 25B, CTQ #19 Because acetaldehyde is the better electrophile, product A is favored. However, we can modify our experiment to exclusively form our unfavored product, B. A. Rosan Chem 350

23.5 Mixed aldol reactions Experimentally, how could you force the desired product to be formed (and not a mixture)? T V I’m not sure ChemAct 26B: CTQ #19 A. Rosan Chem 350

23.3 Dehydration of aldol products In all our aldol reactions so far, we’ve generated the β-hydroxyaldehyde. This product can react further, under more vigorous conditions, to undergo a dehydration or condensation reaction. This is an ______________ reaction. Q: What other (side) product is generated in a condensation reaction? A. Rosan Chem 350

23.3 Dehydration of aldol products Example. Draw the mechanism for the condensation reaction under basic conditions. Example. Draw the mechanism for the condensation reaction under acidic A. Rosan Chem 350

23.4 Using aldol reactions in synthesis (& 23.6 Intramolecular) Example. Predict the reactants needed to provide the following products. (Try working backwards - this is retrosynthesis) Can we use its starting material and form a different cyclic product? A. Rosan Chem 350

The aldol involves 2 aldehydes or 1 aldehyde and 1 ketone. How would this mechanism change if we were to use 2 esters? Claisen! A. Rosan Chem 350

23.7 The Claisen condensation Example. Draw the mechanism for the following reaction (many steps should resemble the aldol reaction). Q: Which is more acidic: the α-hydrogens of the starting material or product? (CQ) Q: What step shifts the equilibrium to the right? (CQ) A. Rosan Chem 350

23.7 The Claisen condensation Which is more acidic: the α-hydrogens of the ester (reactant) or the α-hydrogens of the Claisen product? Ester β-ketoester I’m not sure A. Rosan Chem 350

23.7 The Claisen condensation Which mechanistic step of the Claisen condensation shifts the equilibrium to the right? The formation of the enolate The addition of the enolate to the other ester The breakdown of the tetrahedral intermediate to reform carbonyl Deprotonation of the Claisen product I’m not sure A. Rosan Chem 350

23.7 The Claisen condensation Q: What might happen if I use NaOMe instead of NaOEt? (Predict products) A. Rosan Chem 350

23.7 The Claisen condensation We learned the acetoacetic ester synthesis last chapter. We can use the Claisen to synthesize the starting material! Now we can alkylate and decarboxylate to “substituted” acetone. Example. Synthesize the acetoacetic ester using the Claisen condensation. Get from Claisen! A. Rosan Chem 350

23.9 Intramolecular Claisen: Dieckmann cyclization Example. Predict the product. Draw the mechanism. Show all arrows, charges, and relevant resonance structures. A. Rosan Chem 350

23.9 Intramolecular Claisens: Dieckmann cyclization Which of the following cannot be synthesized by using either a Claisen or Dieckmann condensation? I’m not sure A. Rosan Chem 350

Q: We know that aldol reactions can lead to a mixture of products Q: We know that aldol reactions can lead to a mixture of products. Can Claisen condensations? A. Rosan Chem 350

23.6 Mixed Claisen condensation ChemActivity 26 Read Model 12 on p469 and answer CTQs#40-42. A. Rosan Chem 350

23.6 Mixed Claisen condensation Example. The following Claisen products have been provided for the mixed reaction below. Which C-C bond is new for each product? Which substrate (A/Z) is the nucleophile? Which is the electrophile? Nu E+ A + Z Z + Z A Z Z + A A + A A. Rosan Chem 350

23.10 Conjugate carbonyl addition REVIEW: What type of addition will occur with a 1° amine and an α,β-unsaturated ketone? 1,2 addition 1,4 addition I’m not sure A. Rosan Chem 350

23.10 Conjugate carbonyl addition: Michael addition ChemActivity 26 Read Model 15 on p471 and answer CTQs#50, 52-53. For CTQ #53, your Michael acceptors should resemble the ones in the box! A. Rosan Chem 350

23.10 Conjugate carbonyl addition: Michael addition ChemActivity 26 Read Model 15 on p471 and answer CTQs#50, 52-53. For CTQ #53, your Michael acceptors should resemble the ones in the box! A. Rosan Chem 350

23.11 Carbonyl condensations with enamines: Stork Is this enamine a nucleophile or electrophile? (Which functional group does this resemble?) Nucleophile Electrophile I’m not sure A. Rosan Chem 350

23.11 Carbonyl condensations with enamines: Stork Example. Predict the product for the following reaction. Provide the mechanism for the nucleophilic addition. A. Rosan Chem 350

23.12 Robinson annulation The Robinson annulation (ring formation) is the combination of a Michael addition and intramolecular aldol. Example. Draw the mechanism and predict the product for the following reaction. Example. Determine the reactants needed to obtain the following products. A. Rosan Chem 350

Problems 23.39 and 23.40 A. Rosan Chem 350

How to synthesize Estrone A. Rosan Chem 350

Problem 23. 43 How does this transformation work ? A. Rosan Chem 350

Problem 23.28 How to make via aldol reaction ? A. Rosan Chem 350

Problem 23.41 How do you synthesize … A. Rosan Chem 350

Problem 23.44 How do you make these using a Stork enamine reaction and intramolecular aldol reaction ? A. Rosan Chem 350

Problem 23.62 A. Rosan Chem 350

Problem 23.45, 23.62 A. Rosan Chem 350