Aldehydes

1
Aldehydes Ketones
Chapter 16

• Chapter 16

2
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)

3
16.1 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.

4
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.

O
O
O
5
16.2 A. 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.

6
B. Nomenclature Aldehydes

• the IUPAC retains the common names benzaldehyde
  and cinnamaldehyde, as well formaldehyde and
  acetaldehyde.

7
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 CO the smaller number.
• the IUPAC retains the common names acetone,
  acetophenone, and benzophenone.

8
Order of Precedence, Table 16.1

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

9
C. 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.

10
16.3 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.

11
Preparation of aldehydes and ketones

• Review of methods previously seen in 3010.
• Oxidation of alkenes with conc. KMnO4
• Oxidation of alkenes with O3
• Oxidation of 1o alcohols with PCC
• Oxidation of 2o alcohols with Na2Cr2O4 H2SO4
• Oxidation of glycols with HIO4
• Hydroysis of alkynes
• Hydroboration/oxidation of alkynes

12
16.4 Reaction Themes , Nu attack at C

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

13
Reaction Themes , O attack at H

• 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.

14
Reaction Themes, stereochemistry

• 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.

15
16.5 Addition 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
A. 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, 1o alcohols

• addition of a Grignard reagent to formaldehyde
  followed by H3O gives a 1 alcohol.
• Note that these reactions require two steps.

18
Grignard Reagents, 2o alcohols

• addition to any other aldehyde, RCHO, gives a
  2 alcohol (two steps).

19
Grignard Reagents, 3o alcohols

• addition to a ketone gives a 3 alcohol (two
  steps).

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.
• Work backwards to get starting materials.

21
Grignard Reagents

• Problem 2-phenyl-2-butanol can be synthesized
  by three different combinations of a Grignard
  reagent and a ketone. Show each combination.
• Look at
• Acetophenone Propiophenone 2-butanone
• EtMgBr MeMgBr PhMgBr

22
B. Organolithium Compounds

• Organolithium compounds, RLi, give the same CO
  addition reactions as RMgX but generally are more
  reactive and usually give higher yields.
• Lithium is monovalent and does not insert between
  C and X like Mg.
• Like the Grignard this requires two steps.

23
C. Salts of Terminal Alkynes

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

24
Salts of Terminal Alkynes

• Addition of water or hydroboration/oxidation
• of the product gives an enol which rearranges.

25
D. 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.

O

N
N
H
26
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.

27
Cyanohydrins

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

28
Cyanohydrins

• The value of cyanohydrins
• 3. acid-catalyzed hydrolysis of the nitrile gives
  a carboxylic acid.

N

29
16.6 Wittig Reaction

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

30
Phosphonium Ylides (Wittig reagent)

• 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 CO 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 Modification - Omit

• Horner-Emmons-Wadsworth modification
• uses a phosphonoester.
• phosphonoester formation requires two steps (see
  next slide).

35
Wittig Reaction Modification - Omit

• phosphonoesters are prepared by successive SN2
  reactions
• attack by the phosphite, then
• attack by Br-

36
Wittig Reaction Modification - Omit

• treatment of a phosphonoester with a strong base
  produces the modified Wittig reagent,
• an aldehyde or ketone is then added to give an
  alkene.
• a particular value of using a phosphonoester-stabi
  lized anion is that they are almost exclusively E
  selective.

37
16.7 A. Addition of H2O, hydrates

• 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, hydrates

• when formaldehyde is dissolved in water at 20C,
  the carbonyl group is more than 99 hydrated.
• the equilibrium concentration of a hydrated
  ketone is considerably smaller.

39
B. Addition of Alcohol, hemiacetals

• 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.

40
Addition of Alcohols, in base

• Formation of a hemiacetal can be base catalyzed.
• Step 1 proton transfer 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.

41
Addition of Alcohols, in acid

• Formation of a hemiacetal can be 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.

42
Addition of Alcohol, cyclic hemiacetals

• hemiacetals are only minor components of an
  equilibrium mixture, except where a five- or
  six-membered ring can form.

43
Addition of Alcohol, cyclic hemiacetals

• at equilibrium, the b anomer of glucose
  predominates because the -OH group on the
  anomeric carbon is equatorial.

44
Addition of Alcohols, acetals

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

45
Addition of Alcohols, acetals

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

46
Addition of Alcohols, acetals

• 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, cyclic acetals

• with ethylene glycol and other glycols, the
  product is a five-membered cyclic acetal.
• these are used as carbonyl protective groups.

48
Dean-Stark Trap, Fig. 16.1
49
C. Acetals as Protecting Grps

• Suppose you wish to bring about a Grignard
  reaction between these compounds.
• But a Grignard reagent prepared from
  4-bromobutanal will self-destruct! (react with
  CO)

50
Acetals as Protecting Groups

• So, first protect the -CHO group as an acetal,
• then do the Grignard reaction.
• Hydrolysis in H, HOH (not shown) removes the
  acetal to give the target molecule.

51
D. Acetals as Protecting Groups

• Tetrahydropyranyl (THP), as a protecting group
  for an alcohol.
• 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.

THP group

O
O
Dihydropyran
52
16.8 A. Addition of Nitrogen Nucleophiles

• Ammonia, 1 aliphatic amines, and 1 aromatic
  amines react with the CO group of aldehydes and
  ketones to give imines (Schiff bases). An imine
  has a CHN bond.

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.
• imine formation
• reduction

N
O

(An imine)
Cyclohexanone
H
N
N
Dicyclohexylamine
(An imine)
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 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.

57
B. 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.

Table 16.4
58
16.9 A. 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
B. Keto-Enol Tautomerism, Table 16.5

• 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
16.10 A. 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.

O
O
2

CH
COH
2
Benzoic acid
Benzaldehyde
66
B. 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.

O
O
O
67
16.11 Reduction

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

Aldehydes
Ketones
O
O
68
A. 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.

H
H
H
H
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 CO 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
B. Catalytic Reduction

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

O
Pt

O
H
1-Butanol
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.

O
H
1-Butanol
74
C. Clemmensen Reduction, in acid

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

75
Wolff-Kishner Reduction, in base

• 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
16.12 A. Racemization

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

77
B. Deuterium Exchange

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

78
C. ?-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, in acid

• 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, in base

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

81
?-Halogenation, in acid

• 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.

82
?-Halogenation, in base

• 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.

83
Review of Spectroscopy

• IR Spectroscopy
• Very strong CO stretch around 1710 cm-1.
• Conjugation lowers frequency.
• Ring strain raises frequency.
• Additional C-H stretch for aldehyde two
  absorptions 2720 cm-1 and 2820 cm-1.
  
  
  
  

84
H1 NMR of butanal
85
C13 NMR of 2-heptanone
86
MS of butanal
87
McLafferty Rearrangement of butanal

• Loss of alkene (even mass number)
• Must have ?-hydrogen

88
Aldehydes Ketones
End Chapter 16