Chapter 16: Aldehydes and Ketones

1
Chapter 16 Aldehydes and Ketones

• Chem 30B
• Lecture 17

2
The Carbonyl Group

• In the remainder of the course, we will study the
  physical and chemical properties of classes of
  compounds containing the carbonyl CO group.
• aldehydes and ketones (Chapter 16)
• carboxylic acids (Chapter 17)
• acid halides, acid anhydrides, esters, amides
  (Chapter 18)

3
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 an H atom and a carbon atom.
• The functional group of a ketone is a carbonyl
  group bonded to two carbon atoms.

5
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.

6
Nomenclature Aldehydes

• The IUPAC naming uses the common names
  benzaldehyde, cinnamaldehyde, formaldehyde and
  acetaldehyde.

7
Nomenclature Ketones

• IUPAC names
• The parent alkane is the longest chain that
  contains the carbonyl group.
• For a ketone, change the suffix -e to -one.
• Number the chain to give CO the smaller number.
• IUPAC uses the common names acetone,
  acetophenone, and benzophenone.

8
Order of Precedence

• For compounds containing more than one
  functional group usually indicated by a suffix

9
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
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
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.

12
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.

13
Reaction Themes

• Often the addition to a carbonyl group will
  produce a new stereocenter.
• If none of the starting materials is chiral and
  the reaction takes place in an achiral
  environment, a racemic mixture will be formed.

14
Chapter 16 Aldehydes and Ketones

• Chem 30B
• Lecture 18

15
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.
• Four common types of carbon nucleophiles are

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?.
• 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
  readily to the carbonyl group of aldehydes and
  ketones.

17
Grignard Reagents

• Addition of a Grignard reagent to formaldehyde
  followed by treatment with 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.

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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 alkyne anion followed by treatment
  with H3O gives an ?-acetylenic alcohol.

23
Hydration 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
• Step 1 Nucleophilic addition of cyanide
• Step 2 Proton transfer gives the cyanohydrin and
  regenerates cyanide ion nucleophile.

26
Cyanohydrins

• Acid-catalyzed dehydration gives an alkene.
• 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
• Step 1 Nucleophilic displacement of iodine by
  triphenylphosphine.
• Step 2 Treatment of the phosphonium salt with a
  very strong base, such as BuLi, NaH, or NaNH2

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Wittig Reaction

• Phosphonium ylides react with aldehydes and
  ketones to give alkenes.
• Step 1 Nucleophilic addition of the ylide to the
  electrophilic carbonyl carbon.
• Step 2 Decomposition of the oxaphosphatane.

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Wittig Reaction

• Examples

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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.

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Wittig Reaction

• Horner-Emmons-Wadsworth modification
• Uses a phosphonoester.

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Wittig Reaction

• Phosphonoesters are prepared by successive SN2
  reactions.

34
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-stabi
  lized anion is that they are almost exclusively E
  selective.

35
Chapter 16 Aldehydes and Ketones

• Chem 30B
• Lecture 19

36
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.
• A gem-diol is also referred to as a hydrate.

37
Addition of H2O

• 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.

38
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.

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Addition of Alcohols

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

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Addition of Alcohols

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

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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.

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Addition of Alcohols

• Step 3 Proton transfer from the alcohol to O-
  gives the hemiacetal and generates a new base
  catalyst.

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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.

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Addition of Alcohols

• Step 3 Proton transfer from the oxonium ion to
  A- gives the hemiacetal and generates a new acid
  catalyst.

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Addition of Alcohols

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

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Addition of Alcohols

• Step 1 Proton transfer from HA gives oxonium
  ion.
• Step 2 Loss of water gives resonance-stabilized
  cation.

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Addition of Alcohols

• Step 3 Reaction of the cation with methanol
  gives the conjugate acid of the acetal.
• Step 4 Proton transfer to A- gives the acetal
  and generates a replacement acid catalyst.

48
Addition of Alcohols

• With ethylene glycol and other glycols, the
  product is a five-membered cyclic acetal.

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Dean-Stark Trap
50
Acetals as Protecting Groups

• Suppose you want to run the 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 (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.

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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).

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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

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Addition of Nitrogen Nucleophiles

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

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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.

57
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.

58
Addition of Nitrogen Nucleophiles

• The carbonyl groups of aldehydes and ketones
  react with hydrazine in a manner similar to their
  reactions with 1 amines.

59
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.

60
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.

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Keto-Enol Tautomerism

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

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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-.

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Keto-Enol Tautomerism

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

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Keto-Enol Tautomerism

• For some molecules, 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.