1. 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!
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2. 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)
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3. 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
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4. 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.
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5. 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
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6. 23.1 Aldol addition reaction
Example. Draw the mechanism and predict the product/s.
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7. 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?)
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8. 23.1 Aldol reaction ChemActivity 26A
Read Model 2 and answer CTQs # on page 460.
Regarding CTQ #6, the same reason applies for each aldehyde.
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9. Aldol is a process not a name !
For many reasons, the aldol reaction
can be annoying and complicated.
Let’s discuss them!
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10. 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
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11. 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
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12. 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
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13. 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
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14. Aldol issues Be careful with the reagents that you use!
LDA irreversibly forms the enolate – do you have enough electrophile left?
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15. 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
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16. 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?
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17. 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!
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18. 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.
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19. 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)
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20. 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)
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21. 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!
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22. 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.
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23. 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
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24. 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?
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25. 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
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26. 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?
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27. The aldol involves 2 aldehydes or 1 aldehyde and 1 ketone.
How would this mechanism change if we were to use 2 esters?
Claisen!
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28. 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)
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29. 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
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30. 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
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31. 23.7 The Claisen condensation
Q: What might happen if I use NaOMe instead of NaOEt? (Predict products)
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32. 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!
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33. 23.9 Intramolecular Claisen: Dieckmann cyclization
Example. Predict the product. Draw the mechanism. Show all arrows,
charges, and relevant resonance structures.
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34. 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
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35. 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?
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36. 23.6 Mixed Claisen condensation
ChemActivity 26
Read Model 12 on p469 and answer CTQs#40-42.
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37. 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
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38. 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
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39. 23.10 Conjugate carbonyl addition: Michael addition
ChemActivity 26
Read Model 15 on p471 and answer CTQs#50,
For CTQ #53, your Michael acceptors should resemble the ones in the box!
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40. 23.10 Conjugate carbonyl addition: Michael addition
ChemActivity 26
Read Model 15 on p471 and answer CTQs#50,
For CTQ #53, your Michael acceptors should resemble the ones in the box!
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41. 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
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42. 23.11 Carbonyl condensations with enamines: Stork
Example. Predict the product for the following reaction. Provide the mechanism for the nucleophilic addition.
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43. 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.
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44. Problems and 23.40
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45. How to synthesize Estrone
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46. Problem 23. 43 How does this transformation work ?
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47. Problem 23.28 How to make via aldol reaction ?
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48. Problem 23.41 How do you synthesize …
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49. Problem How do you make these using a Stork enamine reaction and intramolecular aldol reaction ?
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50. Problem 23.62
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51. Problem 23.45, 23.62
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