Organic Chemistry

1
Organic Chemistry

• William H. Brown Christopher S. Foote

2
Aldehydes Ketones
Chapter 16

• 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, CO
• 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

5
The Carbonyl Group

• pi bonding and pi antibonding MOs for
  formaldehyde.

6
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

7
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, show the
  carbon-carbon double bond by changing 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, name the compound by adding the suffix
  -carbaldehyde

8
Nomenclature Aldehydes
9
Nomenclature Ketones

• IUPAC names
• select as the parent alkane the longest chain
  that contains the carbonyl group
• indicate its presence by changing the suffix -e
  to -one
• number the chain to give CO the smaller number

10
Order of Precedence

• For compounds that contain more than one
  functional group indicated by a suffix

11
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

12
Physical Properties

• Oxygen is more electronegative than carbon (3.5
  vs 2.5) and, therefore, a CO 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

13
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

14
Reaction Themes

• A second common theme is reaction with a proton
  or Lewis acid to form a resonance-stabilized
  cation
• protonation in this manner increases the electron
  deficiency of the carbonyl carbon and makes it
  more reactive toward nucleophiles

15
Addn of C Nucleophiles

• Addition of carbon nucleophiles is one of the
  most important types of nucleophilic additions to
  a CO group a new carbon-carbon bond is formed
  in the process
• We study addition of these carbon nucleophiles

16
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

17
Grignard Reagents

• Addition of a Grignard reagent to formaldehyde
  followed by H3O gives a 1 alcohol

18
Grignard Reagents

• Addition to any other RCHO gives a 2 alcohol

19
Grignard Reagents

• Addition to a ketone 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
Organolithium Compounds

• Organolithium compounds are generally more
  reactive in CO addition reactions than RMgX, and
  typically give higher yields

22
Salts of Terminal Alkynes

• Addition of an acetylide anion followed by H3O
  gives an ?-acetylenic alcohol

23
Salts of Terminal Alkynes
24
Addition of HCN

• HCN adds to the CO 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

25
Addition of HCN

• Mechanism of cyanohydrin formation

26
Cyanohydrins

• The value of cyanohydrins
• acid-catalyzed dehydration of the 2 or 3
  alcohol
• catalytic reduction of the cyano group gives a 1
  amine

27
Wittig Reaction

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

28
Phosphonium Ylides

• Phosphonium ylides are formed in two steps

29
Wittig Reaction

• Phosphonium ylides react with the CO group of an
  aldehyde or ketone to give an alkene

30
Wittig Reaction

• Examples

31
Addition of H2O

• Addition of water (hydration) to the carbonyl
  group of an aldehyde or ketone gives a gem-diol,
  commonly referred to as a hydrate
• when formaldehyde is dissolved in water at 20C,
  the carbonyl group is more than 99 hydrated

32
Addition of H2O

• the equilibrium concentration of a hydrated
  ketone is considerably smaller

33
Addition of Alcohols

• Addition of one molecule of alcohol to the CO
  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

34
Addition of Alcohols

• Hemiacetals are only minor components of an
  equilibrium mixture, except where a five- or
  six-membered ring can form
• (the model is of the trans isomer)

35
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

36
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

37
Addition of Alcohols

• Hemiacetals react with alcohols to form acetals
• Acetal a molecule containing two -OR or -OAr
  groups bonded to the same carbon

38
Addition of Alcohols

• Step 1 proton transfer from HA gives an oxonium
  ion
• Step 2 loss of water gives a resonance-stabilized
  cation

39
Addition of Alcohols

• Step 3 reaction of the cation (a Lewis acid)
  with methanol (a Lewis base) gives the conjugate
  acid of the acetal
• Step 4 (not shown) proton transfer to A- gives
  the acetal and generates a new acid catalyst

40
Addition of Alcohols

• With ethylene glycol, the product is a
  five-membered cyclic acetal

41
Dean-Stark Trap
42
Acetals as Protecting Grps

• Suppose you wish to bring about a Grignard
  reaction between these compounds

43
Acetals as Protecting Grps

• If the Grignard reagent were prepared from
  4-bromobutanal, it would self-destruct!
• first protect the -CHO group as an acetal
• then do the Grignard reaction
• hydrolysis (not shown) gives the target molecule

44
Acetals as Protecting Grps

• 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

45
Addn of S Nucleophiles

• Thiols, like alcohols, add to the CO of
  aldehydes and ketones to give tetrahedral
  carbonyl addition products
• The sulfur atom of a thiol is a better
  nucleophile than the oxygen atom of an alcohol
• A common sulfur nucleophile used for this purpose
  is 1,3-propanedithiol
• the product is a 1,3-dithiane

46
Addn of S Nucleophiles

• The hydrogen on carbon 2 of the 1,3-dithiane ring
  is weakly acidic, pKa approximately 31

47
Addn of S Nucleophiles

• a 1,3-dithiane anion is a good nucleophile and
  undergoes SN2 reactions with methyl, 1 alkyl,
  allylic, and benzylic halides
• hydrolysis gives a ketone

48
Addn of S Nucleophiles

• Treatment of the 1,3-dithiane anion with an
  aldehyde or ketone gives an ?-hydroxyketone

49
Addn of N Nucleophiles

• Ammonia, 1 aliphatic amines, and 1 aromatic
  amines react with the CO group of aldehydes and
  ketones to give imines (Schiff bases)

50
Addn of N 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

51
Addn of N Nucleophiles

• a value of imines is that the carbon-nitrogen
  double bond can be reduced to a carbon-nitrogen
  single bond

52
Addn of N Nucleophiles

• Rhodopsin (visual purple) is the imine formed
  between 11-cis-retinal (vitamin A aldehyde) and
  the protein opsin

53
Addn of N Nucleophiles

• Secondary amines react with the CO 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

54
Addn of N Nucleophiles

• The carbonyl group of aldehydes and ketones
  reacts with hydrazine and its derivatives in a
  manner similar to its reactions with 1 amines
• hydrazine derivatives include

55
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

56
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

57
Keto-Enol Tautomerism

• protonation of the enolate anion on oxygen gives
  the enol form protonation on carbon gives the
  keto form

58
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-

59
Keto-Enol Tautomerism

• Keto-enol equilibria for simple aldehydes and
  ketones lie far toward the keto form

60
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

61
Keto-Enol Tautomerism

• Open-chain ?-diketones are further stabilized by
  intramolecular hydrogen bonding

62
Racemization

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

63
Deuterium Exchange

• Deuterium exchange at an ?-carbon may be
  catalyzed by either acid or base

64
?-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

65
?-Halogenation

• Acid-catalyzed ?-halogenation
• Step 1 acid-catalyzed enolization
• Step 2 nucleophilic attack of the enol on halogen

66
?-Halogenation

• Base-promoted ?-halogenation
• Step 1 formation of an enolate anion
• Step 2 nucleophilic attack of the enolate anion
  on halogen

67
?-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

68
Haloform Reaction

• In the presence of base, a methyl ketone reacts
  with three equivalents of halogen to give a
  1,1,1-trihaloketone, which then reacts with an
  additional mole of hydroxide ion to form a
  carboxylic salt and a trihalomethane

69
Haloform Reaction

• The final stage is divided into two steps
• Step 1 addition of OH- to the carbonyl group
  gives a tetrahedral carbonyl addition
  intermediate and is followed by its collapse
• Step 2 proton transfer from the carbonyl group
  to the haloform anion

70
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

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
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

73
Reduction

• aldehydes can be reduced to 1 alcohols
• ketones can be reduced to 2 alcohols
• the CO group of an aldehyde or ketone can be
  reduced to a -CH2- group

74
Catalytic Reduction

• Catalytic reductions are generally carried out at
  from 25 to 100C and 1 to 5 atm H2

75
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

76
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

77
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

78
NaBH4 Reduction

• The key step in metal hydride reduction is
  transfer of a hydride ion to the CO group to
  form a tetrahedral carbonyl addition compound

79
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)

80
Metal Hydride Reduction

• metal hydride reducing agents do not normally
  reduce carbon-carbon double bonds, and selective
  reduction of CO or CC is often possible

81
Clemmensen Reduction

• refluxing an aldehyde or ketone with amalgamated
  zinc in concentrated HCl converts the carbonyl
  group to a methylene group

82
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

83
Prob 16.19

• Draw a structural formula for the product
  formed by treating each compound with
  propylmagnesium bromide followed by aqueous HCl.

84
Prob 16.20

• Suggest a synthesis of each alcohol from an
  aldehyde or ketone and a Grignard reagent. Under
  each is the number of combinations of Grignard
  reagents and aldehyde or ketone that might be
  used.

85
Prob 16.21

• Show how to prepare this alcohol from the
  three given starting materials.

86
Prob 16.22

• Show how to synthesize 1-phenyl-2-butanol
  from these starting materials.

87
Prob 16.24

• Draw the Wittig reagent formed from each
  haloalkane, and for the alkene formed by treating
  the Wittig reagent with acetone.

88
Prob 16.25

• Show how to bring about each conversion using
  a Wittig reaction.

89
Prob 16.26

• Show two sets of reagents that might be
  combined in a Wittig reaction to give this
  conjugated diene.

90
Prob 16.27

• Wittig reactions with an a-haloether can be
  used for the synthesis of aldehydes and ketones.
  To see this, convert each a-haloether to a Wittig
  reagent, and react the Wittig reagent with
  cyclopentanone followed by hydrolysis in aqueous
  acid.

91
Prob 16.28

• Suggest a mechanism for the reaction of a sulfur
  ylide with a ketone to give an epoxide.

92
Prob 16.29

• Propose a structural formula for compound D and
  for the product C9H14O.

93
Prob 16.30

• Draw a structural formula for the cyclic
  hemiacetal. How many stereoisomers are possible
  for it? Draw alternative chair conformations for
  each possible stereoisomer.

94
Prob 16.31

• Draw structural formulas for the hemiacetal and
  acetal formed from each pair of reagents in the
  presence of an acid catalyst.

95
Prob 16.32

• Draw structural formulas for the products of
  hydrolysis of each acetal in aqueous acid.

96
Prob 16.33

• Propose a mechanism for this reaction. If the
  carbonyl oxygen is enriched with oxygen-18, will
  the oxygen label appear in the cyclic acetal or
  in the water?

97
Prob 16.34

• Propose a mechanism for this acid-catalyzed
  reaction.

98
Prob 16.35

• Propose a mechanism for this acid-catalyzed
  rearrangement.

99
Prob 16.37

• Show how to bring about this conversion.

100
Prob 16.39

• Which compound will cyclize to give the insect
  pheromone frontalin?

101
Prob 16.41

• Draw a structural formula for the product formed
  by treating each compound with (1) the lithium
  salt of the 1,3-dithiane derived from
  acetaldehyde and then (2) H2O, HgCl2.

102
Prob 16.42

• Show how to bring about each conversion using a
  1,3-dithiane.

103
Prob 16.44

• Show how each compound can be synthesized by
  reductive amination of an aldehyde or ketone and
  an amine.

104
Prob 16.45

• Show how to bring about this final step in the
  synthesis of the antiviral drug rimantadine.

105
Prob 16.46

• Draw a structural formula for the
  a-hydroxyaldehyde and a-hydroxyketone with which
  this enediol is in equilibrium.

106
Prob 16.47

• Propose a mechanism for the isomerism of
  (R)-glyceraldehyde to (R,S)-glyceraldehyde and
  dihydroxyacetone.

107
Prob 16.48

• When cis-a-decalone is dissolved in ether
  containing a trace of HCl, the following
  equilibrium is established. Propose a mechanism
  for the isomerization and account for the fact
  that the trans isomer predominates.

108
Prob 16.49

• When this bicyclic ketone is treated with D2O in
  the presence of an acid catalyst, only two of the
  three a-hydrogens exchange. Propose a mechanism
  for the exchange and account for the fact that
  the bridgehead hydrogen does not exchange.

109
Prob 16.51

• Propose a mechanism for the formation of the
  bracketed intermediate and for the formation of
  the sodium salt of cyclopentanecarboxylic acid.

110
Prob 16.52

• If the Favorskii rearrangement is carried out
  using sodium ethoxide in ethanol, the product is
  an ethyl ester. Propose a mechanism for this
  reaction.

111
Prob 16.53

• Propose a mechanism for each step in this
  transformation, and account for the
  regioselectivity of the HCl addition.

112
Prob 16.57

• Show how to convert cyclopentanone to each
  compound.

113
Prob 16.59

• Propose structural formulas for A, B, and C.
  Show how C can also be prepared by a Wittig
  reaction.

114
Prob 16.60

• Given this retrosynthetic analysis, show how to
  synthesize cis-3-penten-2-ol from the three given
  starting materials.

115
Prob 16.61

• Propose a synthesis for Oblivon from acetylene
  and a ketone.

116
Prob 16.62

• Propose a synthesis for Surfynol from acetylene
  and a ketone.

117
Prob 16.63

• Propose a mechanism for this acid-catalyzed
  rearrangement.

118
Prob 16.64

• Propose a mechanism for this acid-catalyzed
  rearrangement.

119
Prob 16.66

• Propose mechanisms for Steps (1) and (4) and
  reagents for Steps (2), (3), and (5).

120
Prob 16.68

• Propose a mechanism for this Lewis acid
  catalyzed isomerization. Account for the fact
  that only a single stereoisomer of isopulegol is
  formed.

121
Aldehydes Ketones
End Chapter 16