Organic Chemistry

1. Organic Chemistry William H. Brown Christopher S. Foote Brent L. Iverson

2. Aldehydes & Ketones Chapter 15

3. The Carbonyl Group In this and several following chapters, we study the physical and chemical properties of classes of compounds containing the carbonyl group, C=O aldehydes and ketones (Chapter 16) carboxylic acids (Chapter 17) acid halides, acid anhydrides, esters, amides (Chapter 18) enolate anions (Chapter 19)

4. The Carbonyl Group the carbonyl group consists of one sigma bond formed by the overlap of sp2 hybrid orbitals and one pi bond formed by the overlap of parallel 2p orbitals pi bonding and pi antibonding MOs for formaldehyde

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

6. Nomenclature IUPAC names: the parent chain is the longest chain that contains the functional 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

7. Nomenclature: Aldehydes

8. Nomenclature: Aldehydes

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

10. 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

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

12. 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

13. Physical Properties Oxygen is more electronegative than carbon (3.5 vs 2.5) and, therefore, a C=O group is polar 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

14. Reaction Themes One of the most common reaction themes of a carbonyl group is addition of a nucleophile to form a tetrahedral carbonyl addition compound

15. Reaction Themes A second common theme is reaction with a proton or other Lewis acid to form a resonance-stabilized cation protonation increases the electron deficiency of the carbonyl carbon and makes it more reactive toward nucleophiles

16. Reaction Themes often the tetrahedral product of addition to a carbonyl is a new chiral center if none of the starting materials is chiral and the reaction takes place in an achiral environment, then enantiomers will be formed as a racemic mixture

17. Addition of C 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 carbon nucleophiles

18. Grignard Reagents Given the difference in electronegativity between carbon and magnesium (2.5 - 1.3), the C-Mg bond is polar covalent, with C?- and Mg?+ in its reactions, a Grignard reagent behaves as a carbanion Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge a carbanion is a good nucleophile and adds to the carbonyl group of aldehydes and ketones

19. Grignard Reagents addition of a Grignard reagent to formaldehyde followed by H3O+ gives a 1� alcohol

20. Grignard Reagents addition to any other RCHO gives a 2��alcohol

21. Grignard Reagents addition to a ketone gives a 3� alcohol

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

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

24. Salts of Terminal Alkynes Addition of an alkyne anion followed by H3O+ gives an ?-acetylenic alcohol

25. Salts of Terminal Alkynes

26. 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

27. Addition of HCN Mechanism of cyanohydrin formation Step 1: nucleophilic addition of cyanide to the carbonyl carbon Step 2: proton transfer from HCN gives the cyanohydrin and regenerates cyanide ion

28. Cyanohydrins The value of cyanohydrins acid-catalyzed dehydration of alcohol gives an alkene catalytic reduction of the cyano group gives a 1� amine

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

30. Phosphonium Ylides Phosphonium ylides are formed in two steps: Step 1: nucleophilic displacement of iodine by triphenylphosphine Step 2: treatment of the phosphonium salt with a very strong base, most commonly BuLi, NaH, or NaNH2

31. Wittig Reaction Phosphonium ylides react with the C=O group of an aldehyde or ketone to give an alkene Step 1: nucleophilic addition of the ylide to the electrophilic carbonyl carbon Step 2: decomposition of the oxaphosphatane

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

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

35. Wittig Reaction phosphonoesters are prepared by successive SN2 reactions

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 (hydration) to the carbonyl group of an aldehyde or ketone gives a geminal diol, commonly referred to a gem-diol gem-diols are also referred to as hydrates

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 base catalyzed Step 1: proton transfer from HOR gives an alkoxide Step 2: attack of RO- on the carbonyl carbon Step 3: proton transfer from the alcohol to O- gives the hemiacetal and generates a new base catalyst

43. Addition of Alcohols Formation of a hemiacetal is also acid catalyzed Step 1: proton transfer to the carbonyl oxygen Step 2: attack of ROH on the carbonyl carbon Step 3: proton transfer from the oxonium ion to A- gives the hemiacetal and generates a new acid catalyst

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: proton transfer from HA gives an oxonium ion Step 2: loss of water gives a resonance-stabilized cation

46. Addition of Alcohols Step 3: reaction of the cation (an electrophile) with methanol (a nucleophile) gives the conjugate acid of the acetal Step 4: proton transfer to A- gives the acetal and generates a new acid catalyst

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

48. Dean-Stark Trap

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

50. Acetals as Protecting Groups a Grignard reagent prepared from 4-bromobutanal will self-destruct! first protect the -CHO group as an acetal then do the Grignard reaction hydrolysis (not shown) gives the target molecule

51. 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 reducting agents it is removed by acid-catalyzed hydrolysis

52. 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)

53. Addition of Nitrogen Nucleophiles Formation of an imine occurs in two steps Step 1: carbonyl addition followed by proton transfer Step 2: loss of H2O and proton transfer to solvent

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

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

56. Addition of Nitrogen Nucleophiles Secondary amines react with the C=O group 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

57. Addition of Nitrogen Nucleophiles the carbonyl group of aldehydes and ketones reacts with hydrazine and its derivatives in a manner similar to its reactions with 1� amines

58. 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

59. 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

60. Keto-Enol Tautomerism protonation of the enolate anion on oxygen gives the enol form; protonation on carbon gives the keto form

61. Keto-Enol Tautomerism acid-catalyzed equilibration of keto and enol tautomers occurs in two steps Step 1: proton transfer to the carbonyl oxygen Step 2: proton transfer to the base A-

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

63. 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

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

65. 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

66. 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

67. 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

68. 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

69. 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

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

71. 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)

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

73. 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

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

75. 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

76. Racemization Racemization at an ?-carbon may be catalyzed by either acid or base

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

78. ?-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

79. ?-Halogenation Acid-catalyzed ?-halogenation Step 1: acid-catalyzed enolization Step 2: nucleophilic attack of the enol on halogen Step 3: (not shown) proton transfer to solvent completes the reaction

80. ?-Halogenation Base-promoted ?-halogenation Step 1: formation of an enolate anion Step 2: nucleophilic attack of the enolate anion on halogen

81. ?-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

82. Aldehydes & Ketones