1. Carbonyl Condensation Reactions
Chapter 23
Carbonyl Condensation Reactions
Suggested Problems – 1-22,27-31,41,48-9,58,62-65

2. Condensation Reactions
In carbonyl condensation reactions, the carbonyl compound behaves both as an electrophile and as a nucleophile

3. Carbonyl Condensations: The Aldol Reaction
Carbonyl condensation reactions involve:
Two carbonyl partners
A series of nucleophilic addition and -substitution steps
In a carbonyl condensation reaction, one partner is converted into an enolate-ion nucleophile and adds to the electrophilic group of the second partner
An -substitution reaction occurs in the nucleophilic partner and a nucleophilic addition occurs in the electrophilic partner

4. The General Mechanism of a Carbonyl Condensation Reaction

5. Carbonyl Condensations: The Aldol Reaction
An aldol reaction is a base-catalysed carbonyl condensation reaction that occurs in aldehydes and ketones with an  hydrogen atom
The term aldol comes from the product formed, which contains an aldehyde and an alcohol
The aldol reaction is a reversible reaction.

6. The Equilibrium of the Aldol
Structure of the substrate and the reaction conditions determine aldol equilibrium
In the absence of an -substituent, the product is favored and in cases of disubstituted aldehydes and ketones, the reactant is favored
Steric factors are believed to be the cause as steric congestion in the product is caused by increased substitution

7. Aldehydes and Ketones and the Aldol Equilibrium
Substitution in the alpha position of aldehydes shifts the equilibrium in the favor of reactants. Ketones similarly favor reactants.

8. Worked Example
Predict the aldol reaction product in the compound below:

9. Worked Example Solution:
Forming the enolate of one molecule of the carbonyl compound

10. Worked Example Solution:
Have the enolate attack the electrophilic carbonyl of a second molecule

11. Carbonyl Condensations versus Alpha Substitutions
Carbonyl condensations and  substitutions have similar experimental conditions
Control of experimental conditions is necessary in determining the outcome of a reaction
In an -substitution reaction, a strong base is used and the conditions created ensure that the carbonyl compound quickly converts to an enolate ion at a low temperature
When we generate an enolate ion with the intention of carrying out an alpha alkylation, how can be be sure that a carbonyl condensation reaction won’t occur instead?
Alpha substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature. No unreacted ketone remains, meaning that no condensation reaction could take place. An electrophile is then added rapidly to ensure that the reactive enolate ion is quenched quickly and completely.
Carbonyl condensation reactions require only a catalytic amount of a relatively weak base, rather than a full equivalent, so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound. Once a condensation occurs, the basic catalyst is regenerated. Running the reaction at a higher temperature permits formation of the aldol product.

12. Carbonyl Condensations versus Alpha Substitutions
In a carbonyl condensation, a catalytic amount of a relatively weak base is required
Result is the formation of a small amount of enolate ion in the presence of unreacted carbonyl compound

13. Dehydration of Aldol Products: Synthesis of Enones
The -hydroxy carbonyl products easily dehydrate to yield conjugated enones
The term condensation is based on the fact that water condenses during the formation of an enone product

14. Dehydration of Aldol Products: Synthesis of Enones
Dehydration in aldol products is due to their carbonyl group
The  hydrogen is removed by a base yielding an enolate ion that expels the –OH leaving group
In acidic conditions, the –OH group is protonated and water is expelled

15. Dehydration of Aldol Products: Synthesis of Enones
Conjugated enones are more stable than nonconjugated enones
The reaction conditions needed for an aldol dehydration are often only a bit more vigorous (slightly higher temperature, for instance) than the conditions needed for the aldol formation itself. As a result, conjutgated enones are usually obtained directly from the aldol reactions without isolating the intermediate beta-hydroxy carbonyl compounds.

16. Controlling Aldol Equilibrium
Removal of water from the aldol reaction mixture can be used to drive the aldol equilibrium toward the product
Even though the initial aldol step itself may be unfavorable (as it is for ketones), the subsequent dehydration step allows many aldol condensations to be carried out in good yield

17. Worked Example
Draw the two enone products, excluding double-bond isomers, that result in the aldol condensation of 3-methylcyclohexanone

18. Worked Example Solution:
Including double bond isomers, 4 products can be formed
The major product is formed by the reaction of the enolate formed by abstraction of a proton at position “a”
Position “b” has more steric hindrance

19. Worked Example

20. Using Aldol Reactions in Synthesis
Experimental conditions determine the product of the aldol reaction
Working backwards may help to predict when the aldol reaction may be useful in synthesis
If a desired molecule contains either a -hydroxy carbonyl or a conjugated enone, it might come from an aldol reaction
The aldol reaction yields either a beta-hydroxy aldehyde/ketone or an alpha,beta-unsaturated aldehyde/ketone, depending on the experimental conditions. Whenever the target molecule contains either of these functionalities, it might come from an aldol reaction.

21. Extending the Synthesis
Subsequent transformations can be carried out on the aldol products
Here, two steps following an initial aldol reaction obfuscate the fact that an aldol reaction was employed earlier. One needs to be flexible in realizing that simple transformations may be made on the initial aldol products.

22. Worked Example
Determine whether 2-hydroxy-2-methylpentanal is an aldol condensation product
Identify its aldehyde or ketone precursor
Solution:
This product results from the aldol self-condensation of 3-pentanone, followed by dehydration

23. Mixed Aldol Reactions
A mixed aldol reaction between two similar aldehyde or ketone partners leads to a mixture of four possible products

24. Practical Mixed Aldols
A mixed aldol reaction is possible when:
One of the carbonyl partners have no  hydrogens
An unhindered carbonyl group is present
The presence of a hindered carbonyl group and/or the absence of alpha hydrogens in one of the aldol partners forces the aldol reaction to occur in only one way.

25. Practical Mixed Aldols
A successful mixed aldol reaction is also possible when one of the carbonyl partners is transformed preferentially into its enolate ion owing to the fact that it has a higher acidity than exists in the other carbonyl partner

26. Practical Mixed Aldols
Determine if the following compound can be prepared by a mixed aldol reaction
Show the reactant that can be used

27. Worked Example Solution:
This mixed aldol will succeed because one of the components, benzaldehyde, is a good acceptor of nucleophiles, yet has no -hydrogen atoms
Although it is possible for acetone to undergo self-condensation, the mixed aldol reaction is more highly favored

28. Intramolecular Aldol Reactions
Treatment of certain dicarbonyl compounds with base produces cyclic products by an intramolecular reaction

29. Mechanism of Intramolecular Aldol Reactions
Similar to that of intermolecular reactions
Difference is that the same molecule houses both the nucleophilic carbonyl donor and the electrophilic carbonyl acceptor
The characteristics of the enolate formed controls the end result of the reaction
A mixture of products can be formed

30. Intramolecular Aldol Reaction of 2,5-hexanedione
The formation of five or six membered rings in organic chemistry is generally favored over the formation of three or four membered rings due to the strain in the smaller ring sizes which makes them less stable than their larger ring size cogeners.

31. Worked Example
Determine the product from base treatment of 1,6-cyclodecanedione

32. Worked Example Solution:
This intramolecular aldol condensation gives a product with a seven-membered ring fused to a five-membered ring

33. Claisen Condensation Reaction
Occurs between two ester molecules
An ester with an  hydrogen undergoes reversible carbonyl condensation reaction when treated with 1 equivalent of a base resulting in a -keto ester

34. Mechanism of the Claisen Condensation Reaction

35. Mechanism of the Claisen Condensation Reaction
Note the reversibility of each step in the process.

36. Features of the Claisen Condensation
If the starting ester has more than one acidic  hydrogen, the product -keto ester has a doubly activated hydrogen atom that can be abstracted by base
Requires a full equivalent of base rather than a catalytic amount
Deprotonation of the product causes a shift in equilibrium over to the side of the product, resulting in high yields
The intially derived beta-keto ester enolate serves as a thermodynamic sink to force the reaction to form products.

37. Worked Example
Determine the product obtained by Claisen condensation of (CH3)2CHCH2CO2Et
Solution:
Writing the two Claisen components in the correct orientation makes it easier to predict the product

38. Mixed Claisen Condensations
Successful when one of the two esters cannot form an enolate ion as it does not possess  hydrogens

39. Causing Claisen-like Reactions in Esters and Ketones
Reactions between esters and ketones result in -diketones
The reaction works best when the ester component has no  hydrogens and thus can’t act as a nucleophilic donor

40. Worked Example
Predict the product in the following Claisen-like mixed reaction

41. Worked Example Solution:
Dimethyl oxalate is a very efficient reagent in mixed Claisen reactions

42. Intramolecular Claisen Condensations: The Dieckmann Cyclization
Just as intramolecular aldol condensations can be carried out with diketones
Effective Dieckmann cyclization reactions occur with 1,6-diesters and 1,7-diesters
Five and six membered rings result from these reactions.

43. Mechanism of the Dieckmann Cyclization
Mechanistically these are very similar to traditional Claisen condensations. A cyclic beta-keto ester results.

44. Mechanism of the Dieckmann Cyclization

45. Alkylating the Product of the Dieckmann Reaction
The cyclic -keto ester can be further alkylated and decarboxylated as in the acetoacetic ester synthesis

46. Worked Example
Determine the product of the reaction below

47. Worked Example
Solution:

48. Conjugate Carbonyl Additions: The Michael Reaction
Process in which a nucleophilic enolate ion reacts with an ,-unsaturated compound, producing a conjugate addition product

49. Optimal Conditions for the Michael Reaction
Involve a particularly stable ion and an unhindered ,-unsaturated ketone

50. Mechanism of the Michael Reaction
The driving force behind the conjugate addition observed in this reaction is the formation of a very stable enolate that favors formation of the conjugate addition product.

51. Generality of the Michael Reaction
Occurs with a variety of ,-unsaturated carbonyl compounds (aldehydes, esters, nitriles, amides, and nitro compounds)
Donors include -diketones, -keto esters, malonic esters, -keto nitriles, and nitro compounds
Best reactions take place when a stable enolate ion, such as that derived from a beta-keto ester or other 1,3-dicarbonyl compounds, adds to an unhindered ,-unsaturated ketone.

52. Some Michael Acceptors and Some Michael Donors
Note the stability of the enolate that results following initial Michael initial addition into the Michael acceptors listed on this slide.

53. Worked Example
Predict the product obtained from a base-catalysed Michael reaction of 3-buten-2-one with the nucleophilic donor below

54. Worked Example
Solution:

55. Carbonyl Condensations with Enamines: The Stork Reaction
Enamines are prepared from a ketone and a secondary amine
Enamines are condensation products between a secondary amine and a ketone. The equilibrium is driven toward product formation by removal of water. Addition of water to an enamine results in reformation of the amine and ketone.

56. Enamines Are Nucleophilic
Overlap of the nitrogen lone-pair orbital with the double-bond  orbitals increases electron density on the  carbon atom
Note the similarity between enamines and enolates.

57. Enamine Addition and Hydrolysis
Enamine adds to an ,-unsaturated carbonyl acceptor
Product is hydrolyzed to a 1,5-dicarbonyl compound
The net effect of the Stork reaction is the Michael addition of a ketone to an alpha,beta-unsaturated carbonyl compound.

58. Advantage of Enamine Reactions
The enamine-Michael reaction has two advantages over the enolate-ion–Michael reaction that makes it particularly useful in biological pathways.
Enamine is neutral, easily prepared, and easily handled; an enolate is charged, sometimes difficult to prepare, and must be handled carefully.
Enamine from a monoketone can be used in the Michael addition, whereas only enolate ions from beta-dicarbonyl compounds can be used.
The net effect of the Stork reaction is the Michael addition of a ketone to an alpha,beta-unsaturated carbonyl compound.

59. Worked Example
Use an enamine reaction to prepare the compound below

60. Worked Example Solution:
Analyze the product for the Michael acceptor and the ketone
The Michael acceptor is propenenitrile
The ketone is cyclopentanone, which is treated with pyrrolidine to form the enamine
Carbonyl condensations with enamines: The Stork reaction

61. Worked Example

62. The Robinson Annulation Reaction
A two-step process
It combines a Michael reaction with an intramolecular aldol reaction
The reactants required are a nucleophilic donor, an enamine, and an ,-unsaturated ketone acceptor
The product of a Robinson annulation is a cyclohexenone.

63. Synthesis of the Steroid Hormone Estrone

64. Worked Example
Determine the product of a Robinson annulation reaction of 2-methyl-1,3-cyclopentanedione with 3-buten-2-one
The Robinson annulation reaction

65. Worked Example Solution: The Robinson annulation is a combination of:
A Michael reaction
Reaction between a nucleophilic donor (diketone) and an ,-unsaturated carbonyl compound (enone)
An aldol reaction
Involves the product of the Michael reaction

66. Worked Example
Consider the pKas in this reaction. The pKa of the enolate derived from the diketone is about 9. The pKa of ethoxide is about 15. Which one is more basic? What is the pKa of the methyl group in the Michael acceptor? It’s around 19. Which anion is going to predominate when the three of these are mixed? When the initial aldol reaction occurs and there is a carbanion generated in the initial product, it has a pKa of about 19 as well. Because it is more basic, it abstracts a proton from the ethanol in the solution effectively quenching itself. Now the methyl group on the other side of the carbonyl can be deprotonated. Even though it’s pKa is considerably higher than that of ethoxide, a small amount (perhaps 0.1%) can form as a result of an equilibrium. Once it condenses with the ketone carbonyl group, the equilibrium is essentially driven in the direction of the product. Heating the reaction then drives off water.

67. Some Biological Carbonyl Condensation Reactions
Biological aldol reactions are widely found in carbohydrate metabolism
Type I aldolases are present mostly in animals and higher plants

68. Some Biological Carbonyl Condensation Reactions
Type II aldolases are present mostly in fungi and bacteria
Aldolase-catalysed reactions are mixed aldol reactions that occur between two different partners
The distinction between a type I and a type II aldolase is that the former involves an enamine intermediate and the latter requires a metal ion (usually Zn2+) as Lewis acid and operates through an enolate ion.

69. Biological Claisen Condensations
They are prevalent in many biological pathways
Fatty acid biosynthesis
ACP stands for acyl carrier protein