1. Chapter 20
Aldehydes and Ketones
Suggested Problems –

2. Ketones and Aldehydes Common in biomolecules
Important in the synthesis of many pharmaceuticals
The carbonyl group is common to both ketones and aldehydes

3. Relevant Examples
Identify the following as either an aldehyde or a ketone
Shows relevant examples and gives students practice recognizing the structural difference between aldehydes and ketones
Steroids

4. Nomenclature of Aldehydes
Identify and name the parent chain
For aldehydes, replace the e with an al
Example:
Be sure that the parent chain includes the carbonyl carbon

5. Nomenclature of Aldehydes
Identify and name the parent chain
Numbering the carbonyl group of the aldehyde takes priority over other groups
Example:

6. Nomenclature of Aldehydes
Identify and name the parent chain
Identify the name of the substituents (side groups)
Assign a locant (number) to each substituents
Assemble the name alphabetically
Example: Name the following molecule
E-7-hydroxy-3-propylhept-4-enal

7. Nomenclature of Ketones
Identify and name the parent chain
For ketones, replace the e with an one
Example:
The locant (number showing where the C=O is located) can be expressed before the parent name or before the suffix

8. Nomenclature of Ketones
Identify and name the parent chain
Identify the name of the substituents (side groups)
Assign a locant (number) to each substituents
Assemble the name alphabetically
Example: Name the following molecule
Practice with SkillBuilder 20.1
E-1-hydroxy-5-propyloct-3-en-2,6-dione

9. Preparing Aldehydes and Ketones
Some of the text from tables 20.1 and 20.2 could be removed so that the structures could be larger. Instructor could briefly explain these reactions.

10. Carbonyls as Electrophiles
What makes the carbonyl carbon a good electrophile?
Resonance – there is a minor but significant contributor that includes a formal 1+ charge on the carbonyl carbon

11. Carbonyls as Electrophiles
What makes the carbonyl carbon a good electrophile?
Induction – The carbonyl carbon is directly
attached to a very electronegative oxygen atom
Sterics - How does an sp2 carbon compare to an sp3?

12. Carbonyls as Electrophiles
Consider the factors: resonance, induction, and sterics
Which should be more reactive as an electrophile, aldehydes or ketones? Explain WHY?
Example comparison:
Induction and sterics

13. Nucleophilic attack on a Carbonyl
We want to analyze how nucleophiles attack carbonyls and why some nucleophile react and others don’t
If the nucleophile is weak, or if the attacking nucleophile is a good leaving group, the reverse reaction will dominate
Example attack:
Reverse reaction:

14. Nucleophilic addition
If the nucleophile is strong enough to attack and NOT a good leaving group, then the full addition will occur (mechanism 20.1)
The intermediate carries a negative charge, so it will pick up a proton to become more stable

15. Nucleophilic attack on a Carbonyl
If the nucleophile is weak and reluctant to attack the carbonyl, HOW could we improve its ability to attack?
We can make the carbonyl more electrophilic!
Consider the factors that make it electrophilic in the first place (resonance, induction, and sterics)
Adding an acid will help. HOW?

16. Nucleophilic addition
With a weak nucleophile, the presence of an acid will make the carbonyl more attractive to the nucleophile so the full addition can occur (mechanism 20.2)

17. Nucleophilic attack on a Carbonyl
Is there a reason why acid is not used with strong nucleophiles?

18. Water as a nucleophile
Is water generally a strong or weak nucleophile?
Show a generic mechanism for water attacking an aldehyde or ketone
Predict whether the nucleophilic attack is product favored or reactant favored. WHY?
Would the presence of an acid improve the reaction?
Product disfavored by both entropy and enthalpy (formation of charges).
YES, it would activate the carbonyl

19. Water as a nucleophile
If water were to attack the carbonyl, what likely mechanism steps would follow?
Will the overall process be product or reactant favored? See next slide for examples

20. Water as a nucleophile
Acetone
Formaldehyde
Hexafluoroacetone

21. Water as a nucleophile Acetone Formaldehyde
How do these factors affect the equilibria: entropy, induction, sterics?
Acetone
Formaldehyde
Hexafluoroacetone

22. Water as a nucleophile
The reaction can be catalyzed by a base (mechanism 20.3)

23. Water as a nucleophile
The reaction can also be catalyzed by an acid (mechanism 20.4)

24. Acetal Formation An alcohol acts as the nucleophile instead of water
Notice that the reaction is under equilibrium and that it is acid catalyzed
Analyze the complete mechanism (mechanism 20.5) on the next slide

25. Acetal Formation

26. Acetal Formation Product favored Reactant favored
Practice with SkillBuilder 20.2
5 and 6-membered cyclic acetals are generally product favored

27. Acetal Formation How do entropy, induction, sterics, and
LeChateleir’s Principle affect the equilibrium?
Product favored
Reactant favored
5 and 6-membered cyclic acetals are generally product favored

28. Acetal Equilibrium control
Acetals can be attached and removed fairly easily
Example:
Both the forward and reverse reactions are acid catalyzed
How does the presence of water affect which side the equilibrium will favor?

29. Acetal Protecting Groups
We can use an acetal to selectively protect an aldehyde or ketone from reacting in the presence of other electrophiles
Fill in necessary reagents or intermediates

30. Acetal Protecting Groups
Fill in necessary reagents or intermediates

31. Acetal Protecting Groups
Fill in necessary reagents or intermediates

32. Primary Amine nucleophiles
As a nucleophile, are amines stronger or weaker than water?
If you want an amine to attack a carbonyl carbon, will a catalyst be necessary?
Will an acid (H+) or a base (OH–) catalyst be most likely to work? WHY?
What will the product most likely look like? Keep in mind that entropy disfavors processes in which two molecules combine to form one
Analyze the complete mechanism (mechanism 20.6) on the next slide

33. Primary Amine nucleophiles

34. Primary Amine nucleophiles
The mechanism requires an acid catalyst. Note that the optimal pH to achieve a fast reaction is around 4 or 5
Practice with SkillBuilder 20.3

35. Primary Amine nucleophiles
Why does the reaction slow down at pH below 4?
Why does the reaction slow down at pH greater than 5?

36. Secondary vs. Primary Amines
A proton transfer alleviates the +1 charge in both mechanisms. The difference occurs in the last step
1 ° AMINE (mechanism 20.6): the NITROGEN atom loses a proton directly
2 ° AMINE (mechanism 20.7): a neighboring CARBON atom loses a proton
Practice with SkillBuilder 20.4

37. Wolff-Kishner Reduction
Reduction of a carbonyl to an alkane
Hydrazine attacks the carbonyl via mechanism 20.6 to form the hydrazone, which is structurally similar to an imine
The second part of the mechanism is shown on the next slide (mechanism 20.8)

38. Wolff-Kishner Reduction
In general, carbanions are unstable and reluctant to form

39. Wolff-Kishner Reduction
What drives this reaction forward?
Loss of N2

40. Hydrolysis of Acetals, Imines, and Enamines
Hydrolysis (using water to break bonds) can occur with an acid catalyst
See mechanism on next slide

41. Hydrolysis of Acetals, Imines, and Enamines
How can the equilibrium be controlled to give either acetal formation or hydrolysis?

42. Hydrolysis of Acetals, Imines, and Enamines
Hydrolysis of imines and enamines undergoes a very similar mechanism under acidic conditions
Hydrolysis is not effective when a base is used as the catalyst

43. Sulfur nucleophiles
Under acidic conditions, thiols react nearly the same as alcohols. Examples:

44. Alternative to Wolff-Kishner
Conditions to convert a ketone into an alkane
1) a thioacetal is formed via an acid catalyzed nucleophilic addition mechanism
2) Raney Ni transfers H2 molecules to the thioacetal converting it into an alkane
Recall the Clemmenson (Section 19.6) reduction can also be used to promote this conversion

45. Hydrogen nucleophiles
We rarely see hydrogen acting as a nucleophile. WHY? What role does hydrogen normally play in mechanisms?
To be a nucleophile, hydrogen must have a pair of electrons. H:1- is called hydride
Reagents that produce hydride ions include LiAlH4 and NaBH4. Hydride will react readily with carbonyls

46. Hydrogen nucleophiles
Identify the nucleophile
Will the reaction be more effective under acidic or under basic conditions? WHY?
Show a complete mechanism (mechanism 20.9)
Describe necessary experimental conditions

47. Carbon nucleophiles Carbon doesn’t often act as a nucleophile. WHY?
To be a nucleophile, carbon must have a pair of electrons it can use to attract an electrophile
Examples:
A carbanion with a -1 charge and available pair of electrons. However, carbanions are relatively unstable and reluctant to form
A carbon attached to a very low electronegativity atom such as a Grignard. Analyze the electrostatics of the Grignard reagent c

48. Grignard Example Identify the nucleophile
Will the reaction be more effective under acidic or under basic conditions? WHY?
Show a complete mechanism (mechanism 20.10). Three equivalents of the Grignard are necessary
Describe necessary experimental conditions (why are there two steps in the reaction?)

49. Cyanohydrin The cyanide ion can act as a nucleophile
Disadvantage: EXTREME toxicity and volatility of hydrogen cyanide

50. Cyanohydrin
Advantage: synthetic utility

51. Wittig Reaction
Like the Grignard and the cyanohydrin, the Wittig reaction can be very synthetically useful. What do these three reactions have in common?
Example:
Similar to the Grignard, one carbon is a nucleophile and the other is an electrophile
Identify which is which

52. Wittig Reagent or YLIDE
The ylide carries a formal negative charge on a carbon

53. Wittig Reagent or YLIDE
In general, carbons are not good at stabilizing a negative charge. Are there any factors that allow the ylide to stabilize its formal negative charge?
Why is the charged resonance contributor the major contributor?

54. Wittig Reaction The Wittig mechanism (mechanism 20.12)
Which of the steps in the reaction is mostly likely the slowest? WHY?
The formation of the especially stable triphenylphoshine oxide drives the equilibrium forward

55. Formation of an ylide
To make an ylide, you start with an alkyl halide and triphenylphosphine
Example:
The first step is a simple substitution. The second step is a proton transfer

56. Formation of an ylide
Is the base used in the second step strong or weak? Why is such a base used?

57. Wittig Reaction Overall
Overall, the Wittig reaction allows two molecular segments to be connected through a C=C. Example:
Describe the reagents and conditions necessary for the reaction to take place
Give a mechanism
Note how the colored segments are connected

58. Wittig Reaction Overall
Overall, the Wittig reaction allows two molecular segments to be connected through a C=C. Example:

59. Wittig Reaction Overall
Overall, the Wittig reaction allows two molecular segments to be connected through a C=C
Use a retrosynthetic analysis to determine a different set of reactants that could be used to make the target
Practice with SkillBuilder 20.6

60. Wittig Reaction Overall
Overall, the Wittig reaction allows two molecular segments to be connected through a C=C
Use a retrosynthetic analysis to determine a different set of reactants that could be used to make the target

61. Baeyer-Villiger
An oxygen is inserted between a carbonyl carbon and neighboring group

62. Baeyer-Villiger Example
If the carbonyl is asymmetrical, use the following chart to determine which group migrates most readily
Predict the product of the reaction, and give a complete mechanism

63. Baeyer-Villiger Example
Use the following chart to determine which group migrates most readily
Predict the product, and give a complete mechanism

64. Synthetic Strategies Recall the questions we ask to aid our analysis
Is there a change in the carbon skeleton?
Is there a change in the functional group?
Changes to carbon skeleton:
C-C bond
formation
Name each
reaction

65. Synthetic Strategies Recall the questions we ask to aid our analysis
Is there a change in the carbon skeleton?
Is there a change in the functional group?
Changes to carbon skeleton: Carbon-Carbon bond cleavage – name the reaction
Practice with SkillBuilder 20.7

66. Infrared Spectroscopy
STRONG peak for the C=O stretch
typical carbonyl typical conjugated carbonyl
Aldehydes also give WEAK peaks around cm-1 for the C-H stretch

67. NMR Spectroscopy
Protons neighboring a carbonyl are weakly deshielded by the oxygen
Aldehyde protons are strongly deshielded usually appearing around 9 or 10 ppm. Why is the aldehyde proton shifted so far downfield?
In the 13C NMR, the carbonyl carbon generally appears around 200 ppm

68. Additional Practice Problems
Give a reasonable name for the molecule with both an aldehyde and ketone below.
(S)-3,3-dichloro-4-cyclohexyl-heptan-6-oneal

69. Additional Practice Problems
Give necessary reagents to make the carbonyl below from an alkyne and also from an alkyl halide without altering the number of carbons

70. Additional Practice Problems
Predict the major product and give a complete mechanism.

71. Additional Practice Problems
Predict the major product and give a complete mechanism.

72. Additional Practice Problems
Predict the structure of the enamine product in the reaction below and show the last step of the mechanism.

73. Additional Practice Problems
Give necessary Wittig reagents to synthesize the molecule below and show a complete mechanism.

74. Additional Practice Problems
Give necessary Wittig reagents to synthesize the molecule below and show a complete mechanism.

75. Additional Practice Problems
Give reagents necessary for the synthesis below

76. Additional Practice Problems
Give reagents necessary for the synthesis below
Alternative synthesis