1. The Carbonyl Group
In this and several following chapters, we study the physical and chemical properties of classes of compounds containing the carbonyl C=O group.
Aldehydes and ketones (Chapter 19)
Carboxylic acids (Chapter 20)
Carboxylic acids Derivatives (Chapter 21)

2. Structure
The functional group of an aldehyde is a carbonyl group bonded to an H atom and a carbon atom.
The functional group of a ketone is a carbonyl group bonded to two carbon atoms.

3. Nomenclature IUPAC names:
The parent chain is the longest chain that contains the carbonyl group.
For an aldehyde, change the suffix from -e to -al.
For an unsaturated aldehyde, change the infix from an- to -en-; the location of the suffix determines the numbering pattern.
For a cyclic molecule in which -CHO is bonded to the ring, add the suffix -carbaldehyde.

4. Nomenclature: Aldehydes
The IUPAC naming retains the common names benzaldehyde and cinnamaldehyde, as well formaldehyde and acetaldehyde.

5. Nomenclature: Ketones
IUPAC names
The parent alkane is the longest chain that contains the carbonyl group.
Indicate the ketone by changing the suffix -e to -one.
Number the chain to give C=O the smaller number.
The IUPAC retains the common names acetone, acetophenone, and benzophenone.

6. Order of Precedence
For compounds that contain more than one functional group indicated by a suffix.

7. Common Names
For an aldehyde, the common name is derived from the common name of the corresponding carboxylic acid.
For a ketone, name the two alkyl or aryl groups bonded to the carbonyl carbon and add the word ketone.

8. Physical Properties
Oxygen is more electronegative than carbon (3.5 compared with 2.5) and, therefore, a C=O bond is polar covalent.
Aldehydes and ketones are polar compounds and interact in the pure state by dipole-dipole interaction.
They have higher boiling points and are more soluble in water than nonpolar compounds of comparable molecular weight. C O – d - + M o r e i m p t a n c b u g s P l y f

9. Reaction Themes
The most common reaction theme of a carbonyl group is addition of a nucleophile to form a tetrahedral carbonyl addition compound.
The carbonyl carbon is highly electrophilic.
These reactions are often referred to as nucleophilic acyl addition to the electrophilic carbonyl carbon.

10. Reaction Themes
A second common theme is reaction with a proton or other Lewis acid to form a resonance-stabilized cation.
Protonation of the carbonyl oxygen increases the electron deficiency of the carbonyl carbon and makes it more electrophilic, that is, more reactive toward nucleophiles.
All proton-transfer reactions are fast and reversible (next screen).

11. Reaction Themes

12. Reaction Themes
Both themes can be predicted on the basis of the large bond dipole of the carbonyl group.
Electrophiles such as H+ are attracted to the partial negative charge of the carbonyl oxygen.
Nucleophiles are attracted to the partial positive charge of the carbonyl carbon.

13. Reaction Themes
Often the tetrahedral product of addition to a carbonyl group is a new chiral center.
If neither of the starting materials is chiral and the reaction takes place in an achiral environment, then enantiomers will be formed as a racemic mixture.

14. Addition of Carbon Nucleophiles
Addition of carbon nucleophiles is one of the most important types of nucleophilic additions to a C=O group.
A new carbon-carbon bond is formed in the process.
We study addition of these four types of carbon nucleophiles

15. Grignard Reagents
Given the difference in electronegativity between carbon and magnesium ( ), the C-Mg bond is polar covalent, with C- and Mg+.
In its reactions, a Grignard reagent behaves as a carbanion.
Each of the previously described carbanion reactions follows the same mechanistic pattern, namely making a bond between the carbon nucleophile and the electrophilic carbonyl carbon atom.

16. Grignard Reagents
Treatment of a Grignard reagent with formaldehyde followed by protonation with H3O+ gives a 1° alcohol.

17. Grignard Reagents
Step 1: Make a new bond between a nucleophile and an electrophile.
Step 2: Add a proton.

18. Grignard Reagents
Treatment of a Grignard reagent with any other aldehyde followed by protonation gives a 2° alcohol.

19. Grignard Reagents
Treatment of a Grignard reagent with a ketone followed by protonation gives a 3° alcohol.

20. Grignard Reagents
Problem: 2-Phenyl-2-butanol can be synthesized by three different combinations of a Grignard reagent and a ketone. Show each combination.

21. Grignard Reagents
Grignard reactions form a new carbon-carbon bond between the R or Ar group and a carbonyl carbon. In this problem there are three different C-C bonds that could be formed: (a), (b), and (c).

22. Organolithium Compounds
Organolithium compounds are generally more reactive than RMgX in C=O addition reactions, and typically give higher yields.

23. Anions of Terminal Alkynes
Addition of the anion of a terminal alkyne to a ketone followed by treatment with H3O+ gives an alkynyl alcohol.

24. Anions of Terminal Alkynes
Hydration of an alkynyl alcohol gives either a ketone or an aldehyde depending on the alkyne and the method of hydration.
Acid catalyzed hydration gives an -hydroxyketone.
Hydroboration-oxidation gives a -hydroxyaldehyde.

25. Addition of HCN
HCN adds to the C=O group of an aldehyde or ketone to give a cyanohydrin.
Cyanohydrin: A molecule containing an -OH group and a -CN group bonded to the same carbon.

26. Addition of HCN
Step 1: Make a new between a nucleophile and and electrophile.
Step 2: Add a proton.

27. Cyanohydrins The value of cyanohydrins
Acid-catalyzed dehydration of the alcohol gives an alkene.
Catalytic reduction of the cyano group gives a 1° amine.

28. Wittig Reaction
The Wittig reaction is a very versatile synthetic method for the synthesis of alkenes from aldehydes and ketones.

29. Phosphonium Ylides
A Phosphonium ylide is formed by treatment of a phosphonium salt with a very strong base, most commonly BuLi, NaH, or NaNH2.

30. Wittig Reaction
Phosphonium ylides react with the C=O groups of aldehydes and ketones to give alkenes.
Step 1: Make a new bond between a nucleophile and an electrophile to give a dipolar intermediate called a betaine.
Step 2: Collapse of the betaine to form a four-membered ring.

31. Wittig Reaction
Step 3: Break a bond to give stable molecules or ions.

32. Wittig Reaction
Examples:

33. Wittig Reaction
Some Wittig reactions are Z selective, others are E selective.
Wittig reagents with an anion-stabilizing group, such as a carbonyl group, adjacent to the negative charge, are generally E selective.
Wittig reagents without an anion-stabilizing group are generally Z selective. O E t P h 3 R e s o n a c r i b u g f y l d z j p

34. Wittig Reaction Horner-Emmons-Wadsworth modification
Uses a phosphonoester.

35. Wittig Reaction
Phosphonoesters are prepared by successive SN2 reactions. ( M e O ) 3 P C H 2 - E t B r + S N A n a p h o s

36. Wittig Reaction
Treatment of a phosphonoester with a strong base followed by an aldehyde or ketone gives an alkene.
A particular value of using a phosphonoester-stabilized anion is that they are almost exclusively E selective.

37. Addition of H2O
Addition of water to the carbonyl group of an aldehyde or ketone gives a geminal diol, commonly referred to a gem-diol.
A gem-diol is also referred to as a hydrate.

38. Addition of H2O
When formaldehyde is dissolved in water at 20°C, the carbonyl group is more than 99% hydrated.
The equilibrium concentration of a hydrated ketone is considerably smaller.

39. Addition of Alcohols
Addition of one molecule of alcohol to the C=O group of an aldehyde or ketone gives a hemiacetal.
Hemiacetal: A molecule containing an -OH and an -OR or -OAr bonded to the same carbon.

40. Addition of Alcohols
Hemiacetals are only minor components of an equilibrium mixture, except where a five- or six-membered ring can form.

41. Addition of Alcohols
At equilibrium, the b anomer of glucose predominates because the -OH group on the anomeric carbon is equatorial.

42. Addition of Alcohols Formation of a hemiacetal is catalyzed by base.
Step 1: Take a proton away.
Step 2: Make a new bond between a nucleophile and an electrophile.
Step 3: Add a proton B - H O R + f a s t n d r e v i b l C H 3 - O – : R + O : – C H 3 - R +

43. Addition of Alcohols Hemiacetal formation is also catalyzed by acid.
Step 1: Add a proton to the carbonyl oxygen.
Step 2: Make a new bond between a nucleophile and an electrophile.
Step 3: Take a proton away. O C H 3 - A + f a s t n d r e v i b l O C H 3 - R + R H C 3 - O A +

44. Addition of Alcohols Hemiacetals react with alcohols to form acetals.
Acetal: A molecule containing two -OR or -OAr groups bonded to the same carbon.

45. Addition of Alcohols
Step 1: Add a proton. Step 2: Break a bond to give stable molecules or ions. H O R - C 3 A : + n o x i u m R - C O H 3 2 + A r e s o n a c t b i l z d

46. Addition of Alcohols
Step 3: Make a new bond between a nucleophile and an electrophile. Step 4: Take a proton away. C H 3 - O R A p r o t n a e d c l + A : - R C O H 3 + ( 4 ) n a c e t l

47. Addition of Alcohols
With ethylene glycol and other glycols, the product is a five-membered cyclic acetal.

48. Addition of Alcohols
Formation of acetals is an equilibrium process, and the position of equilibrium can be manipulated. Using the alcohol as a solvent and, therefore, in large excess forces the equilibrium to the right. Conversely, treating an acetal with a large excess of water brings about acetal hydrolysis.

49. Figure 16.1 A Dean-Stark Trap

50. Acetals as Protecting Groups
Suppose you wish to bring about a Grignard reaction between these compounds.

51. Acetals as Protecting Groups
The Grignard reagent prepared from 4-bromobutanal will self-destruct! To avoid this,
First protect the -CHO group as an acetal.
Then do the Grignard reaction.
Hydrolysis of the acetal (not shown) gives the target molecule.

52. Acetals as Protecting Groups
Tetrahydropyranyl (THP) protecting group.
The THP group is an acetal and, therefore, stable to neutral and basic solutions, and to most oxidizing and reducing agents.
It is removed by acid-catalyzed hydrolysis.

53. Addition of Nitrogen Nucleophiles
Ammonia, 1° aliphatic amines, and 1° aromatic amines react with the C=O group of aldehydes and ketones to give imines (Schiff bases).

54. Addition of Nitrogen Nucleophiles
Formation of an imine occurs in two steps:
Step 1: Make a new bond between a nucleophile and an electrophile.
Step 2: Take a proton away.

55. Addition of Nitrogen Nucleophiles
Step 3: Add a proton.
Step 4: Add a proton

56. Addition of Nitrogen Nucleophiles
Step 5: Break a bond to give stable molecules or ions.
Step 6: Add a proton

57. Addition of Nitrogen Nucleophiles
A value of imines is that the carbon-nitrogen double bond can be reduced to a carbon-nitrogen single bond.

58. Addition of Nitrogen Nucleophiles
Rhodopsin (visual purple) is the imine formed in the eye between 11-cis-retinal (vitamin A aldehyde) and the protein opsin.

59. Addition of Nitrogen Nucleophiles
Secondary amines react with the C=O groups of aldehydes and ketones to form enamines.
The mechanism of enamine formation involves formation of a tetrahedral carbonyl addition compound followed by its acid-catalyzed dehydration.
We discuss the chemistry of enamines in more detail in Chapter 19.

60. Addition of Nitrogen Nucleophiles
The carbonyl groups of aldehydes and ketones react with hydrazine and its derivatives in a manner similar to their reactions with 1° amines.

61. Pyridoxine (B6)
Reversible formation of imines plays a role biological transformations called transaminations.

62. Pyridoxine (B6)
Transaminations are catalyzed by a group of enzymes called transaminases, all of which require pyridoxal phosphate, a coenzyme derived from pyridoxine.

63. Pyridoxine (B6)
The result of transamination is the transfer an amino group (-NH2) from an -amino acid to an -keto acid.

64. Acidity of -Hydrogens
Hydrogens alpha to a carbonyl group are more acidic than hydrogens of alkanes, alkenes, and alkynes but less acidic than the hydroxyl hydrogen of alcohols.

65. Acidity of -Hydrogens
-Hydrogens are more acidic because the enolate anion is stabilized by:
1. Delocalization of its negative charge.
2. The electron-withdrawing inductive effect of the adjacent electronegative oxygen.

66. Keto-Enol Tautomerism
Addition of a proton to oxygen of the enolate anion gives an enol; addition of a proton to carbon gives a ketone.

67. Keto-Enol Tautomerism
Acid-catalyzed equilibration of keto and enol tautomers occurs in two steps.
Step 1: Add a proton.
Step 2: Take a proton away-. O C H 3 - A + K e t o f r m • T h c n j u g a i d k s v b l O C H 3 - 2 : A = E n o l f r m + s w

68. Keto-Enol Tautomerism
Keto-enol equilibria for simple aldehydes and ketones lie far toward the keto form.

69. Keto-Enol Tautomerism
For certain types of molecules, however, the enol is the major form present at equilibrium:
For -diketones, the enol is stabilized by conjugation of the pi system of the carbon-carbon double bond and the carbonyl group.
For acyclic -diketones, the enol is further stabilized by hydrogen bonding.

70. Oxidation of Aldehydes
Aldehydes are oxidized to carboxylic acids by a variety of oxidizing agents, including H2CrO4.
They are also oxidized by Ag+.
In one method, a solution of the aldehyde in aqueous ethanol or THF is shaken with a slurry of silver oxide.

71. Oxidation of Aldehydes
Aldehydes are oxidized by O2 in a radical chain reaction.
Liquid aldehydes are so sensitive to air that they must be stored under N2.

72. Pinnick Oxidation
A selective way to oxidize an aldehyde to a carboxylic acid uses sodium chlorite (NaClO2) with a phosphate buffer (NaH2PO4).
Step 1: Creation of chlorous acid.
Step 2: Add a proton

73. Pinnick Oxidation
Step 3: Make a bond between a nucleophile and an electrophile.
Step 4: Take proton away and simultaneously break a bond to give stable molecules or ions.

74. Pinnick Oxidation
Step 5: Scavenge the hypochlorous acid (as an example using electrophilic addition to an alkene).

75. Oxidation of Ketones
Ketones are not normally oxidized by chromic acid.
They are oxidized by powerful oxidants at high temperature and high concentrations of acid or base.

76. Reduction Aldehydes can be reduced to 1° alcohols.
Ketones can be reduced to 2° alcohols.
The C=O group of an aldehyde or ketone can be reduced to a -CH2- group.

77. Metal Hydride Reduction
The most common laboratory reagents for the reduction of aldehydes and ketones are NaBH4 and LiAlH4.
Both reagents are sources of hydride ion, H:-, a very powerful nucleophile.

78. NaBH4 Reduction
Reductions with NaBH4 are most commonly carried out in aqueous methanol, in pure methanol, or in ethanol.
One mole of NaBH4 reduces four moles of aldehyde or ketone.

79. NaBH4 Reduction
The key step in metal hydride reduction is transfer of a hydride ion to carbon of the C=O group to form a tetrahedral carbonyl addition compound.

80. LiAlH4 Reduction
Unlike NaBH4, LiAlH4 reacts violently with water, methanol, and other protic solvents.
Reductions using it are carried out in diethyl ether or tetrahydrofuran (THF).

81. Catalytic Reduction
Catalytic reductions are generally carried out at from 25° to 100°C and 1 to 5 atm H2.

82. Catalytic Reduction
A carbon-carbon double bond may also be reduced under these conditions.
By careful choice of experimental conditions, it is often possible to selectively reduce a carbon-carbon double in the presence of an aldehyde or ketone.

83. Clemmensen Reduction
Refluxing an aldehyde or ketone with amalgamated zinc in concentrated HCl converts the carbonyl group to a methylene group.

84. Wolff-Kishner Reduction
In the original procedure, the aldehyde or ketone and hydrazine are refluxed with KOH in a high-boiling solvent.
The same reaction can be brought about using hydrazine and potassium tert-butoxide in DMSO.

85. Wolff-Kishner Reduction
Step 1: Reaction of the carbonyl group with hydrazine gives a hydrazone.
Step 2: Take a proton away.

86. Wolff-Kishner Reduction
Step 3: Add a proton.
Step 4: Take a proton away.

87. Wolff-Kishner Reduction
Step 5: Break a bond to give stable molecules or ions.
Step 6: Add a proton.

88. Racemization
Racemization at an -carbon may be catalyzed by either acid or base.

89. Deuterium Exchange
Deuterium exchange at an -carbon may be catalyzed by either acid or base.

90. -Halogenation
-Halogenation: aldehydes and ketones with at least one -hydrogen react at an -carbon with Br2 and Cl2 .
Reaction is catalyzed by both acid and base.

91. -Halogenation Acid-catalyzed -halogenation
Step 1: Acid-catalyzed keto-enol tautomerism.
Step 2: Make a new bond between a nucleophile and an electrophile.
Step 3: (not shown) Take a proton away. H R ' - C O s l o w

92. -Halogenation Base-promoted -halogenation
Step 1: Take a proton away.
Step 2: Make a new bond between a nucleophile ( bond) and an electrophile. • + - R e s o n a c t b i l z d w O H C ' : 2 + f a s t R ' C O B r - :

93. -Halogenation Acid-catalyzed halogenation:
Introduction of a second halogen is slower than the first.
Introduction of the electronegative halogen on the -carbon decreases the basicity of the carbonyl oxygen toward protonation.
Base-promoted -halogenation:
Each successive halogenation is more rapid than the previous one.
The introduction of the electronegative halogen on the -carbon increases the acidity of the remaining -hydrogens and, thus, each successive -hydrogen is removed more rapidly than the previous one.

94. Problem 16.27
Sulfur ylides react with ketones to give epoxides. Suggest a mechanism for this reaction.

95. Problem 16.27
Step 1: Make a bond between a nucleophile and an electrophile.

96. Problem 16.27
Step 2: Make a new bond between a nucleophile and an electrophile and simultaneously break a bond to give stable molecules or ions.