2. 1. Alpha-halogenation of ketones
C
C
H
O
+ X2
OH- or H+
C
C
X
O
+ HX
X2 = Cl2, Br2, I2
-haloketone
H3C
C
CH3
O
+ Br2, NaOH
H3C
C
CH2Br
O
+ NaBr
acetone -bromoacetone
3. O
+ Cl2, H+
O
Cl
+ HCl
2-chlorocyclohexanone
C CH3
O
+ Br2, NaOH C CH2Br + NaBr
O
-bromoacetophenone
cyclohexanone
acetophenone
4. Alpha-hydrogens: 1o > 2o > 3o
CH3CH2CH2CCH3
O
2-pentanone
+ Br2, NaOH CH3CH2CH2CCH2Br + NaBr
O
1-bromo-2-pentanone
Hydrogens that are alpha to a carbonyl group are weakly acidic:
H3C
C
CH3
O
H3C
C
CH2
O
+ OH + H2O
6. Mechanism for base promoted alpha-bromination of acetone:
H3C
C
CH3
O
H3C
C
CH2
O
+ OH + H2O
RDS
H3C
C
CH2
O
+ Br Br
H3C
C
CH2Br
O
+ Br
1)
2)
Rate = k [acetone] [base]
7. Mechanism for acid catalyzed halogenation of ketones. Enolization.
H3C
C
CH3
O
H3C
C
CH3
OH
+ H+
H3C
C
CH3
OH
+ :B
H3C
C
CH2
OH
+ H:B
H3C
C
CH2
OH
+ Br Br
H3C
C
CH2Br
OH
+ :Br
H3C
C
CH2Br
OH
H3C
C
CH2Br
O
+ H
“enol”
1)
2)
3)
4)
8. R
C
CH3
O
Oxidation of "methyl" ketones. Iodoform test.
+ (xs) OI R C
O
O
+ CHI3
NaOH + I2
R
C
CH2I
O
R
C
CHI2
O
R
C
CI3
O
+ OH
R C CI3
O
OH
good
leaving
group
9. Carbanions. The conjugate bases of weak acids;
strong bases, good nucleophiles.
1. enolate anions
2. organometallic compounds
3. ylides
4. cyanide
5. acetylides
10. Aldehydes and ketones: nucleophilic addition
Esters and acid chlorides: nucleophilic acyl substitution
Alkyl halides: SN2
C
O
+ YZ C
OY
Z
C
W
O
+ Z C
Z
O
+ W
R X + Z R Z + X
Carbanions as the nucleophiles in the above reactions.
11. 2. Carbanions as the nucleophiles in nucleophilic
addition to aldehydes and ketones:
a) aldol condensation
“crossed” aldol condensation
b) aldol related reactions (see problem 21.18
on page 811)
c) addition of Grignard reagents
d) Wittig reaction
12. Carbanions as the nucleophiles in nucleophilic addition to
aldehydes and ketones:
c) addition of Grignard reagents
Grignard reagents are examples of organo metallic
carbanions.
C
O
+ RMgX C
OMgX
R
13. a) Aldol condensation. The reaction of an aldehyde or ketone
with dilute base or acid to form a beta-hydroxycarbonyl product.
CH3CH=O
dil. NaOH
CH3CHCH2CH O
OH
acetaldehyde 3-hydroxybutanal
CH3CCH3
O
dil. NaOH
CH3CCH2CCH3
O
OH
CH3
acetone
4-hydroxy-4-methyl-2-pentanone
20. NB: An aldehyde without alpha-hydrogens
undergoes the Cannizzaro reaction with conc. base.
CHO
benzaldehyde
conc. NaOH
COO-
CH2OH
+
21. Crossed aldol condensation:
If you react two aldehydes or ketones together in an
aldol condensation, you will get four products. However, if
one of the reactants doesn’t have any alpha hydrogens it can be
condensed with another compound that does have alpha
hydrogens to give only one organic product in a “crossed”
aldol.
CH3CH2CH + H2C O
O CH3CHCH2 OH
CH O
NaOH
22. N.B. If the product of the aldol condensation under basic
conditions is a “benzyl” alcohol, then it will spontaneously
dehydrate to the α,β-unsaturated carbonyl.
CH=O + CH3CH2CH2CH=O
dil OH-
CH=CCH=O
CH2
CH3
CHCHCH=O
OH
CH2
CH3
-H2O
23. A crossed aldol can also be done between an aldehyde and a
ketone to yield one product. The enolate carbanion from the
ketone adds to the more reactive aldehyde.
C CH3
O
acetophenone
+ CH3CH=O
acetaldehyde
dil OH-
CCH2
O
C
H
OH
CH3
24. b) Aldol related reactions: (see problem 21.18 page 811
of your textbook).
CH=O + CH3NO2
KOH
CH=CHNO2 + H2O
CH2NO2
CH=O + CH2C N
NaOEt
CH=C CN
CHC N
+ H2O
25. Perkin condensation
CH=O + (CH3CO)2O
CH3COONa
CH=CHCOOH
H2C C
O
O
C
CH3
O
CH
OH
CH2 C
O
O
C
CH3
O
+ H2O
H
C C
H
C
O
O
C
CH3
O
hydrolysis of
anhydride
+ CH3COOH
26. d) Wittig reaction (synthesis of alkenes)
1975 Nobel Prize in Chemistry to Georg Wittig
C O + Ph3P=C R'
R
ylide
C
O
C R'
R
PPh3
C C
R
R' + Ph3PO
CH2CH=O + Ph3P=CH2 CH2CH=CH2 + Ph3PO
Ph = phenyl
27. C
O
C R'
R
PPh3
C C
R
R' + Ph3PO
P
Ph
Ph
Ph
C
R
R' C
O
ylide
nuclephilic addition by ylide carbanion, followed by loss of
Ph3PO (triphenylphosphine oxide)
29. 3. Carbanions as the nucleophiles in nucleophilic acyl
substitution of esters and acid chlorides.
a) Claisen condensation
a reaction of esters that have alpha-hydrogens in basic
solution to condense into beta-keto esters
CH3COOEt
ethyl acetate
NaOEt
CH3CCH2COOEt
O
+ EtOH
ethyl acetoacetate
36. b) Coupling of lithium dialkyl cuprate with acid chloride
R C
Cl
O
+ R'2CuLi R C
R'
O
nucleophile = R'
37. 4. Carbanions as nucleophiles in SN2 reactions with R’X:
a) Corey-House synthesis of alkanes
R2CuLi + R’X R-R’
b) metal acetylide synthesis of alkynes
RCC-M+ + R’X RCCR’
c) Malonate synthesis of carboxylic acids
d) Acetoacetate synthesis of ketones
5. Michael Addition to α,β-unsaturated carbonyl
compounds
38. Carbanions are the conjugate bases of weak acids and
are therefore strong bases and excellent nucleophiles
that can react with aldehydes/ketones (nucleophilic
addition), esters/acid chlorides (nucleophilic acyl
substitution), and alkyl halides (SN2), etc.
39. Reactions involving carbanions as nucleophiles:
1. Alpha-halogenation of ketones
2. Nucleophilic addition to aldehydes/ketones
a) aldol and crossed aldol
b) aldol related reactions
c) Grignard synthesis of alcohols
d) Wittig synthesis of alkenes
3. Nucleophilic acyl substitution with esters and acid
chlorides
a) Claisen and crossed Claisen
b) R2CuLi + RCOCl
(next slide)
40. 4. SN2 with alkyl halides
a) Corey-House
b) metal acetylide
c) Malonate synthesis
d) Acetoacetate synthesis
5. Michael Addition to α,β-unsaturated carbonyl
compounds