Nucleophilic Addition to Carbonyls

1
Nucleophilic Addition to Carbonyls
C1

• Revision of Enolization......

2
Nucleophilic Addition to Carbonyls
C2

• Nucleophilic Addition of Enolate Anions

can act as a nucleophile most common site
of reaction is.........
3
Nucleophilic Addition of Enolate Anions
C3

• Halogenation of (nucleophilic) Enolate Anions
• (i.e. halogen is an electrophile E )

4
Nucleophilic Addition of Enolate Anions
C4

• Halogenation of (nucleophilic) Enolate Anions
• reaction not practical except for methylketones
• haloform reaction
• ? spot test for the presence of methyl
  ketones acetaldehyde (CH3CHO) alcohols of the
  type R-CHOH-CH3 (only) - ALSO give positive
  results.

when X I yellow precipitate of CHI3
5
Nucleophilic Addition of Enolate Anions
C5

• Alkylation of (nucleophilic) Enolate
  Anions
• Reactivity of the reaction
• X leaving group
• 2o alcohols react poorly, 3o dont
  react vinylic and aryl halides dont react
• -R

General Example
enolisation
6
Nucleophilic Addition of Enolate Anions
C6

• Alkylation of (nucleophilic) Enolate Anions
• (Specific Example)

LDA lithium diisopropylamide (a strong
base) DME ethylene glycol dimethyl ether
(solvent)
7
Nucleophilic Addition of Enolate Anions
C7

• Alkylation of (nucleophilic) Enolate Anions
  (Specific Example)

8
Nucleophilic Addition of Enolate Anions
C8

• Alkylation of (nucleophilic) Enolate Anions
  (Specific Example)
• NaNH2 sodium amide (a strong base)
• (the use of a strong base is important)

60
9
Nucleophilic Addition of Enolate Anions
C9

• Reaction of Nucleophilic Enolate Anions with
  Carbonyl Compounds
• This reaction is known as the Aldol
  Reaction.......

? ?
a carbonyl compound
an enolate anion
10
Alpha, Beta-Unsaturated Carbonyl Compounds
C10
11
Alpha, Beta-Unsaturated Carbonyl Compounds
C11
???-unsaturated ketone
normal carbonyl
12
Alpha, Beta-Unsaturated Carbonyl Compounds
C12

• Conjugation of the CC bond with the CO, ?
  system is stabilized (as shown by resonance
  structures).
• The electrophilicity of the carbon atom of the
  carbonyl is transferred to the ?-carbon (through
  conjugation).
• ? alkene is electrophilic!!!
• Note alkenes are normally electron rich
  systems?
• ??susceptible to electrophilic attack eg by acids
  (H) or X

13
Alpha, Beta-Unsaturated Carbonyl Compounds
C13

• other examples of electrophilic alkenes.....

nitrile
nitro
carbonyl
14
Alpha, Beta-Unsaturated Carbonyl Compounds
C14

• The electropositive alkene carbon of
  ???-unsaturated carbonyls is susceptible to
  nucleophilic attack
• Attack of nucleophile to CC is a
  conjugate addition or a 1,4-additio
  n
• c.f. nucleophilic attack to a normal carbonyl
  is a1,2-addition

15
Reactions of ?, ?-Unsaturated Carbonyl Compounds
C15

• Attack of Nitrogen Nucleophiles....
• nucleophile is the nitrogen lone electron pair
  on the amine
• mild acid catalysis required (acetic acid)

methyl vinyl ketone
diethylamine
Note product is saturated
16
Reactions of ?, ?-Unsaturated Carbonyl Compounds
C16

• Attack of Nitrogen Nucleophiles....Mechanism

nucleophilic attack at ?-carbon
intermediates stabilized by resonance
17
Reactions of ?, ?-Unsaturated Carbonyl Compounds
C17

• Attack of Sulfur Nucleophiles.....
• similarly......

sulfur nucleophiles (cf oxygen nucleophiles)
18
Reactions of ?, ?-Unsaturated Carbonyl Compounds
C18

• Similarly.....
• Sulfur nucleophiles attack ???-unsaturated
  carbonyls via the same mechanism as nitrogen
  nucleophiles
• Oxygen nucleophiles attack in the same fashion
  via the same mechanism as nitrogen nucleophiles

19
Reactions of ?, ?-Unsaturated Carbonyl Compounds
C19

• further reaction examples.....
• nucleophilic addition to ???-unsaturated triple
  bond carbonylconcept identical

20
Reactions of ?, ?-Unsaturated Carbonyl Compounds
C20

• further reaction examples.....

i.e. different electron withdrawing group
21
Reactions of ?, ?-Unsaturated Carbonyl Compounds
C21

• Addition of OrganometallicsGrignard
  Reagents R-MgBrorOrganocuprates R2CuLi

22
Reactions of ?, ?-Unsaturated Carbonyl Compounds
C22

• Grignard Reagents mainly 1,2 addition
  products (as previously studied)

1,2-addition product
91
23
Reactions of ?, ?-Unsaturated Carbonyl Compounds
C23

• Organocuprate Reagents....
• Copper promotes the addition at electrophilic
  carbonsother than carbonyl carbons!
• generation of reagent

exact structure not known
24
Reactions of ?, ?-Unsaturated Carbonyl Compounds
C24

• Organocuprate Reagents....
• conjugate 1,4-addition
• excess of organocuprate required
• mechanism not understood
• intermediate enolate anion could be further
  utilized

enolate anion from conjugate addition
97