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Aldehydes & Ketones: Nucleophilic Addition to the Carbonyl Group

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1 Aldehydes & Ketones: Nucleophilic Addition to the Carbonyl Group
Chapter 16 Aldehydes & Ketones: Nucleophilic Addition to the Carbonyl Group

2 About The Authors These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang. Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem. Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

3 Introduction Carbonyl compounds

4 Nomenclature of Aldehydes & Ketones
Rules Aldehyde as parent (suffix) Ending with “al”; Ketone as parent (suffix) Ending with “one” Number the longest carbon chain containing the carbonyl carbon and starting at the carbonyl carbon

5 Examples

6 group as a prefix: methanoyl or formyl group
group as a prefix: ethanoyl or acetyl group (Ac) groups as a prefix: alkanoyl or acyl groups


8 Physical Properties

9 Synthesis of Aldehydes
4A. Aldehydes by Oxidation of 1o Alcohols

10 e.g.

11 4B. Aldehydes by Ozonolysis of Alkenes

12 e.g.

13 4C. Aldehydes by Reduction of Acyl Chlorides, Esters, and Nitriles

14 LiAlH4 is a very powerful reducing agent, and aldehydes are easily reduced
Usually reduced all the way to the corresponding 1o alcohol Difficult to stop at the aldehyde stage Not a good method to synthesize aldehydes using LiAlH4

15 Two derivatives of aluminum hydride that are less reactive than LAH


17 Aldehydes from acyl chlorides: RCOCl  RCHO

18 Reduction of an Acyl Chloride to an Aldehyde

19 Aldehydes from esters and nitriles: RCO2R’  RCHO
RC≡N  RCHO Both esters and nitriles can be reduced to aldehydes by DIBAL-H

20 Reduction of an ester to an aldehyde

21 Reduction of a nitrile to an aldehyde

22 Examples

23 Synthesis of Ketones 5A. Ketones from Alkenes, Arenes, and 2o Alcohols
Ketones (and aldehydes) by ozonolysis of alkenes

24 Examples

25 Ketones from arenes by Friedel–Crafts acylations

26 Ketones from secondary alcohols by oxidation

27 5B. Ketones from Nitriles

28 Examples

29 Suggest synthesis of from and

30 Retrosynthetic analysis
5 carbons here 4 carbons here need to add one carbon

31 Retrosynthetic analysis
disconnection disconnection

32 Synthesis

33 Suggest synthesis of from and

34 Retrosynthetic analysis
5 carbons here 5 carbons here no need to add carbon

35 Retrosynthetic analysis

36 Synthesis

37 Nucleophilic Addition to the Carbon–Oxygen Double Bond
Structure Nu⊖ Carbonyl carbon: sp2 hybridized Trigonal planar structure

38 Polarization and resonance structure
Nucleophiles will attack the nucleophilic carbonyl carbon Note: nucleophiles usually do not attack non-polarized C=C bond

39 With a strong nucleophile:

40 Also would expect nucleophilic addition reactions of carbonyl compounds to be catalyzed by acid (or Lewis acid) Note: full positive charge on the carbonyl carbon in one of the resonance forms Nucleophiles readily attack

41 Mechanism

42 Mechanism

43 6A. Reversibility of Nucleophilic Additions to the Carbon–Oxygen Double Bond
Many nucleophilic additions to carbon–oxygen double bonds are reversible; the overall results of these reactions depend, therefore, on the position of an equilibrium

44 6B. Relative Reactivity: Aldehydes vs. Ketones

45 Steric factors small large

46 Electronic factors (positive inductive effect from both R & R' groups)  carbonyl carbon less d+ (less nucleophilic) (positive inductive effect from only one R group)

47 The Addition of Alcohols: Hemiacetals and Acetals
Acetal & Ketal Formation: Addition of Alcohols to Aldehydes Catalyzed by acid

48 Mechanism

49 Mechanism (Cont’d)

50 Mechanism (Cont’d)

51 Note:. All steps are reversible
Note: All steps are reversible. In the presence of a large excess of anhydrous alcohol and catalytic amount of acid, the equilibrium strongly favors the formation of acetal (from aldehyde) or ketal (from ketone) On the other hand, in the presence of a large excess of H2O and a catalytic amount of acid, acetal or ketal will hydrolyze back to aldehyde or ketone. This process is called hydrolysis

52 Acetals and ketals are stable in neutral or basic solution, but are readily hydrolyzed in aqueous acid

53 Aldehyde hydrates: gem-diols

54 Mechanism

55 7A. Hemiacetals Hemiacetal: OH & OR groups bonded to the same carbon

56 Hemiacetal: OH & OR groups bonded to the same carbon

57 7B. Acetals A ketal An acetal

58 Cyclic acetal formation is favored when a ketone or an aldehyde is treated with an excess of a 1,2-diol and a trace of acid

59 This reaction, too, can be reversed by treating the acetal with aqueous acid

60 7C. Acetals Are Used as Protecting Groups
Although acetals are hydrolyzed to aldehydes and ketones in aqueous acid, acetals are stable in basic solutions Acetals are used to protect aldehydes and ketones from undesired reactions in basic solutions

61 Example

62 Synthetic plan This route will not work

63 Reason: (a) Intramolecular nucleophilic addition (b) Homodimerization or polymerization

64 Thus, need to “protect” carbonyl group first

65 7D. Thioacetals Aldehydes & ketones react with thiols to form thioacetals

66 Thioacetal formation with subsequent “desulfurization” with hydrogen and Raney nickel gives us an additional method for converting carbonyl groups of aldehydes and ketones to –CH2– groups

67 The Addition of Primary and Secondary Amines
Aldehydes & ketones react with 1o amines to form imines and with 2o amines to form enamines From a 1o amine From a 2o amine

68 8A. Imines Addition of 1o amines to aldehydes & ketones

69 Mechanism

70 Similar to the formation of acetals and ketals, all the steps in the formation of imine are reversible. Using a large excess of the amine will drive the equilibrium to the imine side Hydrolysis of imines is also possible by adding excess water in the presence of catalytic amount of acid

71 8B. Oximes and Hydrazones
Imine formation – reaction with a 1o amine Oxime formation – reaction with hydroxylamine

72 Hydrazone formation – reaction with hydrazine
Enamine formation – reaction with a 2o amine

73 8C. Enamines

74 Mechanism

75 Mechanism (Cont’d)

76 Mechanism (Cont’d)

77 The Addition of Hydrogen Cyanide: Cyanohydrins
Addition of HCN to aldehydes & ketones

78 Mechanism

79 Slow reaction using HCN since HCN is a weak acid and a poor source of nucleophile
Can accelerate reaction by using NaCN or KCN and slow addition of H2SO4

80 Synthetic applications

81 The Addition of Ylides: The Wittig Reaction

82 Phosphorus ylides

83 Example

84 Mechanism of the Wittig reaction

85 10A. How to Plan a Witting Synthesis
Synthesis of using a Wittig reaction

86 Retrosynthetic analysis

87 Synthesis – Route 1

88 Synthesis – Route 2

89 10B. The Horner–Wadsworth–Emmons Reaction


91 The phosphonate ester is prepared by reaction of a trialkyl phosphite [(RO)3P] with an appropriate halide (a process called the Arbuzov reaction)

92 Oxidation of Aldehydes

93 Chemical Analyses for Aldehydes and Ketones
12A. Derivatives of Aldehydes & Ketones

94 12B. Tollens’ Test (Silver Mirror Test)

95 Spectroscopic Properties of Aldehydes and Ketones
13A. IR Spectra of Aldehydes and Ketones

96 Conjugation of the carbonyl group with a double bond or a benzene ring shifts the C=O absorption to lower frequencies by about 40 cm-1


98 13B. NMR Spectra of Aldehydes and Ketones
13C NMR spectra The carbonyl carbon of an aldehyde or ketone gives characteristic NMR signals in the d 180–220 ppm region of 13C spectra

99 1H NMR spectra An aldehyde proton gives a distinct 1H NMR signal downfield in the d 9–12 ppm region where almost no other protons absorb; therefore, it is easily identified Protons on the a carbon are deshielded by the carbonyl group, and their signals generally appear in the d 2.0–2.3 ppm region Methyl ketones show a characteristic (3H) singlet near d 2.1 ppm



102 Summary of Aldehyde and Ketone Addition Reactions

103  END OF CHAPTER 16 

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