Carbonyl Chemistry

1
Carbonyl Chemistry
C1

• Part I
• Nomenclature
• General Properties
• Carbonyls as Bases
• Enolization
• Preparation of Aldehydes
• Preparation of Ketones
• Reactivity of Carbonyls
• Nucleophilic Addition Reactions
• Nucleophilic Substitution Reactions

2
Carbonyl Chemistry
C2

• Chemistry of aldehydes ketones
• The carbonyl group
• planar
• polarized
• carbon is sp2 hybridized

3
Carbonyl Nomenclature Aldehydes
C3

• formaldehyde acetaldehyde
• as a substituent (e.g. on a ring) aromatic

Aldehydes suffix -al
methanal
ethanal
benzaldehyde
cyclohexanecarbaldehyde
4
Carbonyl Nomenclature Ketones
C4

• propanone methyl ethyl ketone
• a phenone

acetone
2-butanone
Ketones suffix -one
cyclopentanone
acetophenone
5
Carbonyl Nomenclature
C5

• Indicating positions relative to a
  carbonyl
• should a carbonyl need to be named as a
  substituentuse oxo
• e.g.

6
Carbonyls as Bases
C6

• Protonation of the carbonyl oxygen
• positive charge enhances electrophilicity of the
  carbonyl group ? increase in reactivity

7
Carbonyls as Bases
C7

• Lewis acids are often used (e.g. AlCl3)

Specific example
8
Carbonyls as Acids
C8

• ?-hydrogen (to the carbonyl) can be removed with
  a base.
• carbanion stabilized by delocalizat
  ion
• enolate anions

keto / enol are tautomers
9
Enolization
C9

• for acetone.......
• for penta-2,4-dione......(stabilized by
  diketo-delocalization)

almost exclusively in keto form
significant proportion in enol form
10
Enolization
C10

• .....already seen base catalyzed enolization
  (previous slides)
• acid catalyzed enolization also possible.

11
Preparation of Aldehydes
C11

• Mild Oxidation of Primary Alcohols
• e.g. pyridinium chlorochromate in
  dichloromethane
• Ozonolysis of AlkenesNote at least one
  vinylic hydrogen is needed

12
Preparation of Aldehydes
C12

• Partial Reduction of Carboxylic AcidsDIBAH
  diisobutylaluminiumhydride

13
Preparation of Ketones
C13

• Oxidation of Secondary Alcohols
• can use - Jones reagent (CrO3 in aq. H2SO4)
• - sodium dichromate
• - PCC
• Ozonolysis of Disubstituted Alkenes

70
14
Preparation of Ketones
C14

• Friedel-Crafts Reaction for Aryl Ketones
• Hydration of Terminal Alkynes
• - requires catalytic mercuric ion
• - methyl ketones are produced

15
Reactivity of the Carbonyl
C15

• The ? carbonyl carbon is susceptible to
  nucleophilic attack
• two product types are possible
• substituted products or addition products

?-
O
O
OH

• subn

• addn

C
?
C
C
R
X
Nu
R
X
R
Nu
Nu
16
Addition vs Substitution
C16

• Substitution
• When Y is a good leaving group, substitution is
  favoured

O
O
O
Nu
Y


C
R
Y
C
C
R
Nu
R
Y
Nu
17
Carbonyl Substitution Reactions
C17

• Factors influencing Nucleophilic attack........
• Steric hinderence the more highly substituted
  the carbonyl, the less susceptible to Nu
  attack
• Electronegativity the more electronegative
  Y....the greater the ? on the carbonyl
  carbon ? the more reactive to Nu attack

18
Carbonyl Substitution Reactions
C18
O
O
O
O
(CH3)3CCCl
(CH3)2CHCCl
CH3CH2CCl
CH3CCl
increasing reactivity
O
O
O
C
C
C
CH3
NH2
OH
CH3
Cl
CH3
acetamide
acetic acid
acetyl chloride
19
Carbonyl Addition Reactions
C19

• Addition Reactions
• If Y cannot stabilize a -ve charge, it is a
  poor leaving group? Nu attacks yields addition
  products
• e.g. if Y H leaving group would be a hydride
  ion
• if Y CH3 leaving group would be a 1o methyl
  ion
• both examples are not stablized ? are poor
  leaving groups
• ? Nu addition reaction occurs

OH
O
O
H
Nu
C
R
Y
C
R
Y
C
R
Y
Nu
Nu
20
Nucleophilic Addition Reactions of Carbonyls

• Nucleophilic addition of HCN
• - formation of Cyanohydrins
• - use of carbon nucleophiles
• Note synthetic utility in addition of 1 x
  extra carbon
• addition of 2 x functional groups

21
Nucleophilic attack by Cyanide Ions
C21

• specific example

nitrile hydrolysis
cyano-reduction yielding an amine
lactic acid
22
Functional Group Interconversions
C22

• consider the previous example

23
C23

• Further examples of the nucleophilic addition of
  cyanide ions

an aldehyde
a ketone
24
Nucleophilic Addition Reactions of Carbonyls
C24

• Nucleophilic addition of Organometallic
  Nucleophiles

Organometallic nucleophiles are carbon
nucleophiles
Organometallic nucleophiles
Grignard reagents
organolithium reagents
e.g. R-MgBr
e.g. R-Li
25
Organolithium Reagents as Carbon Nucleophiles
C25
carbon nucleophile can attack electrophilic
centre
specific example
26
Organolithium Reagents as Carbon Nucleophiles
C26

• specific example

100
27
Grignard Reagents as Carbon Nucleophiles
C27

• General Reaction......
• carbonyls that can be reacted

28
Reactions of Grignards with......
C28

• with carbon dioxide....
• with formaldehyde....

carboxylic acid
Note addition of one (1) extra carbon
primary alcohol
29
Reactions of Grignards with......
C29

• with aldehydes....
• with ketones....

secondary alcohol
tertiary alcohol
30
Reactions of Grignards with......
C30

• with esters....

tertiary alcohol
31
Nucleophilic Addition Reactions of Carbonyls
C31

• Hydrides as Nucleophiles
• hydride source reducing agents
• e.g. LiAlH4 - lithium aluminiun hydride
• NaBH4 - sodium borohydride

hydride H- is basic a very strong
nucleophile
32
Hydrides as Nucleophiles Examples
C32

• all four hydrides (H-) from the borohydride
  are used
• LiAlH4 NaBH4 do NOT reduce isolated double
  bonds

95
33
Nucleophilic Addition Reactions of Carbonyls
C33

• Nucleophilic Addition by Oxygen Containing
  Species
• Hydrates, Acetals Ketals

Reactions of aldehydes with alcohols
Reactions of ketones with alcohols
Reaction with water
34
Nucleophilic Addition Reactions of Carbonyls
C34

• Reactions with Water Formation of Hydrates
• general example

35
Nucleophilic Addition Reactions of Carbonyls
C35

• Hydrate formation (reactions with water) Specific
  Examples

acetone hydrate
formaldehyde
formaldehyde hydrate
36
Nucleophilic Addition Reactions of Carbonyls
C36

• Reactions of Alcohols with Aldehydes Acetal
  Formation
• General Example

aldehyde
hemiacetal
acetal
37
Nucleophilic Addition Reactions of Carbonyls
C37

• Reactions of Alcohols with Aldehydes Acetal
  Formation
• Specific Example

aldehyde
38
Nucleophilic Addition Reactions of Carbonyls
C38

• Reactions of Alcohols with Ketones Acetal
  Formation
• General Example

ketone
39
Nucleophilic Addition Reactions of Carbonyls
C39

• Reactions of Alcohols with Ketones Acetal
  Formation
• Specific Example
• hemiacetals hemiketals are unstable (and
  reversible)
• unless both functional groups are part of the
  same molecule

0.3
40
Nucleophilic Addition Reactions of Carbonyls
C40

• Reactions of Alcohols with Aldehydes Acetal
  Formation

glucose as hydroxyaldehyde
glucose as stable hemiacetal
41
Nucleophilic Addition Reactions of Carbonyls
C41

• for acetals ketals.....
• reverse reaction is simply hydrolysis in the
  presence of acid
• Mechanism of acetal/ketal formation
  hydrolysis.........

42
Nucleophilic Addition Reactions of Carbonyls
C42

• Nucleophilic Addition of Thiols
• R-OH
• c.f. R-SH
• products are generally more stable
• General Example
• (Raney nickel will reduce any R-s group to R-H)

43
Nucleophilic Addition Reactions of Carbonyls
C43

• Nucleophilic Addition of Thiols
• Specific Example
• Note no strong acids or bases required
  (important with sensitive molecules)

44
Nucleophilic Substitution Reactions of Carbonyls
C44

• Nucleophilic Substitution by Nitrogen Containing
  Species

45
Nucleophilic Substitution Reactions of Carbonyls
C45

• Preparation of Derivatives
• oximes
• hydrazones

46
Preparation of Derivatives
C46

• semicarbazones
• 2,4-dinitrophenylhydrazine (DNP)

benzaldehyde semicarbazone (mp 222o)