1. Chapter 23 Carbonyl Condensation Reactions

2. Condensation
Is a Chemical reaction in which two molecules or (functional groups) combine to form one single molecule, together with the loss of a small molecule. Usually water molecule.

3. Most common condensation reaction occurs between Carbonyl group and amino group such as condensation between two amino acids to form peptide.

4. Condensation between hydrazine hydrate or phenyl hydrazine with aldehydes and ketones to form characteristic hydrazones and with di carbonyl compound to form heterocyclic ring.

5. Also reaction of alcohols and acids which known as esterification is considered a condensation process because it involves a production of water molecule

6. Alpha Substitution Rxns (Ch. 22)

7. Carbonyl Condensation Rxns
Treatment of acetaldehydes with strong base leads to formation of aldol

9. Deuterium Exchange in Carbonyl compounds

12. The Aldol Condensation

15. The Mixed Aldol Condensation

16. b) Aldol condensation
Under the influence of or , two molecules of an aldehyde or a ketone, which , may combine to form a β-Hydroxy aldehyde or β-Hydroxy ketone. This reaction is called the
dilute base
dilute acid
contained α-hydrogen
Aldol condensation

17. Mechanism:

18. If aldehyde or ketone does not contain an α-hydrogen, a simple Aldol condensation cannot take place.
For example:

19. Outline
Aldol
Carbonyl Condensation
Micheal Reaction
Claisen

20. 1. Carbonyl Condensation
Carbonyl compounds are both the electrophile and nucleophile in carbonyl condensation reactions

21. Aldol Condensation
Acetaldehyde reacts in basic solution (NaOEt, NaOH) with another molecule of acetaldehyde
The b-hydroxy aldehyde product is aldol (aldehyde + alcohol)
This is a general reaction of aldehydes and ketones

22. General Condensations

23. Mechanism of Aldol Reactions
Aldol reactions, like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule
The addition intermediate is protonated to give an alcohol product

24. Predicting Aldol Products
The product will have an alcohol and a carbonyl in a 1,3 relationship (a beta-hydroxy carbonyl)

25. 1. Claisen Condensation Condensation of Two Ester Molecules.
The product of a Claisen condensation is a β-keto ester.
In a Claisen condensation, one molecule of carbonyl compound is the nucleophile and second molecule is electrophile.
The new C-C bond connect the α-carbon of one molecule and the carbon that was formerly the carbonyl carbon of the other molecule

27. Mechanism of the Claisen Condensation
Similar to aldol condensation: nucleophilic acyl substitution of an ester enolate ion on the carbonyl group of a second ester molecule
If the starting ester has more than one acidic a hydrogen, the product -keto ester has a doubly activated proton that can be abstracted by base
Requires a full equivalent of base rather than a catalytic amount
The deprotonation drives the reaction to the product

28. Learning Check:
Predict the product of Claisen condensation of ethyl propanoate

29. Solution:
Predict the product of Claisen condensation of ethyl propanoate

30. Mixed Claisen Condensations
Successful when one of the two esters acts as the electrophilic acceptor in reactions with other ester anions to give mixed -keto esters

31. 2.Conjugate Carbonyl Additions: The Michael Reaction
Enolates can add as nucleophiles to ,-unsaturated aldehydes and ketones to give the conjugate addition product

32. Mechanism of the Michael
Nucleophilic addition of a enolate ion donor to the  carbon of an ,-unsaturated carbonyl acceptor

33. Learning Check:
Make the following using a Michael Reaction:

34. Solution:
Make the following using a Michael Reaction:

35. Learning Check:
Which of the following statements explains why the following aldehyde will not undergo an aldol reaction with itself?
The benzene ring makes the carbonyl group unreactive towards aldol reactions.
A carbonyl group must be connected to two alkyl groups in order to undergo an aldol reaction.
The molecule does not possess any hydrogens α to the carbonyl group.
Electrophilic aromatic substitution competes favorably with the aldol reaction.
Nucleophilic acyl substitution competes favorably with the aldol reaction.

36. Solution:
Which of the following statements explains why the following aldehyde will not undergo an aldol reaction with itself?
The benzene ring makes the carbonyl group unreactive towards aldol reactions.
A carbonyl group must be connected to two alkyl groups in order to undergo an aldol reaction.
The molecule does not possess any hydrogens α to the carbonyl group.
Electrophilic aromatic substitution competes favorably with the aldol reaction.
Nucleophilic acyl substitution competes favorably with the aldol reaction.

37. Predict the aldol reaction product of the following ketone.
Learning Check:
Predict the aldol reaction product of the following ketone. 1. 2. 3. 4. 5. 1 2 3 4 5

38. Predict the aldol reaction product of the following ketone.
Solution:
Predict the aldol reaction product of the following ketone. 1. 2. 3. 4. 5. 1 2 3 4 5

39. What type of reaction occurs in a Claisen condensation?
Learning Check:
What type of reaction occurs in a Claisen condensation?
electrophilic aromatic substitution
nucleophilic addition
hydrolysis
nucleophilic acyl substitution
decarboxylation

40. What type of reaction occurs in a Claisen condensation?
Solution:
What type of reaction occurs in a Claisen condensation?
electrophilic aromatic substitution
nucleophilic addition
hydrolysis
nucleophilic acyl substitution
decarboxylation

41. Learning Check:
Select the correct Claisen condensation product for the following reaction. 1. 3. 2. 5. 4. 1 2 3 4 5

42. Predict the outcome of the following reaction.
Solution:
Predict the outcome of the following reaction. 1. 2. 3. 5. 4. 1 2 3 4 5

43. Alkylation of Aldehydes and Ketones
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Alkylation of Aldehydes and Ketones
Alkylation of enolates can be difficult to control.
The alkylation of an aldehyde or ketone enolate is an example of a nucleophilic substitution reaction.

44. The alkylation of aldehydes and ketones is complicated by several unwanted side reactions.
E2 elimination: Enolate ion is a fairly strong base. Alkylation is normally feasible using only halomethanes or primary haloalkanes.
Condensation Reactions: Aldehyde alkylations usually fail because their enolate ions undergo a highly favorable condensation reaction.
Multiple Alkylations: Even ketones may lose a second -hydrogen and become alkylated a second time.
Regioisomeric Products: If the starting ketone is unsymmetrical, either -carbon may be alkylated.

45. An example of a successful alkylation of a ketone:
The ketone possesses a single -hydrogen and the primary allylic halide is an excellent SN2 substrate.

46. Enamines afford an alternative route for the alkylation of aldehydes and ketones.
Secondary amines react with aldehydes or ketones to produce enamines.
The nitrogen substituent renders the enamine carbon-carbon double bond electron-rich.
This electron density is concentrated at the -carbon, which makes it nucleophilic.

47. As a result of its nucleophilicity, electrophiles may attack the -carbon of the enamine.
Enamines will react with haloalkanes resulting in alkylation at carbon to produce an iminium salt.
The iminium salt is hydrolyzed during aqueous work-up, liberating the newly alkylated aldehyde or ketone and the original secondary amine.

48. Alkylation of an enimine is far superior to the alkylation of an enolate.
Minimizes multiple alkylations: The iminium salt formed after the first alkylation is unable to react with additional haloalkane.
It can be used to prepare alkylated aldehydes (aldehyde enolates undergo aldol condensation reactions).

49. Attack by Enolates on the Carbonyl Function: Aldol Condensation
23-5
Attack by Enolates on the Carbonyl Function: Aldol Condensation
Aldehydes undergo base-catalyzed condensations.
Treating an aldehyde at low temperature with a small amount NaOH results in the formation of dimer, which, when heated, is converted into an ,-unsaturated aldehyde.
This reaction is known as an aldol condensation. It is general for aldehydes and sometimes succeeds with ketones.

50. The hydroxide ion serves as a catalyst for the reaction.
The overall reaction is not very exothermic and yields are only 50-60%.

51. At elevated temperatures, the aldol is converted into its enolate ion, which loses hydroxide (normally a poor leaving group) to form the relatively stable final product.

52. The aldol condensation yields different products depending upon the reaction temperature.
Low temperatures: a -hydroxycarbonyl compound
Higher temperatures: an ,-unsaturated carbonyl compound

53. Ketones can undergo aldol condensation.
The driving force of the aldol reaction of ketones is less than that of aldehydes because of the greater stability of ketones (about 3 kcal mol-1). The reaction is endothermic.
The reaction can be driven towards completion by the continuous extraction of alcohol, or under more vigorous conditions, dehydration and the removal of water.

54. Crossed Aldol Condensation
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Crossed Aldol Condensation
An aldol condensation between the enolate of one aldehyde and the carbonyl of another results in a crossed aldol condensation.
Enolates of both aldehydes will be present and may react with the carbonyl groups of either starting compound.

55. A single aldol product can be obtained from the reaction of two different aldehydes when one of them has no enolizable hydrogen atoms.
The reaction is carried out by slowly adding the enolizable aldehyde to an excess of the nonenolizable reactant in the presence of a base.

56. Intramolecular Aldol Condensation
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Intramolecular Aldol Condensation
An intramolecular aldol condensation results from the reaction of an enolate ion and a carbonyl group within the same molecule.
Reaction between different aldehyde molecules is minimized by running the reaction in a dilute solution.
The kinetics of intramolecular 5-membered ring formation are also favorable.

57. Intramolecular ring closures of ketones are a ready source of cyclic and bicyclic ,-unsaturated ketones.
Usually the least strained ring is formed (typically 5- or 6-membered).
Intramolecular aldol condensations of ketones succeed while intermolecular condensations fail because of the more favorable entropy change for ring closure (1 molecule  1 molecule rather than 2 molecules  1 molecule).