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Me Me
O
D3C CD3
OD3O+
Me Me
O
Me CH2
OH
Me CH2
O
H
H2O
OH2
Mechanism:
Me CH2
OH
the keto form the enol form
Me Me
O
H+
H
D OD2
Me CH2
O
D
repeat 5 times
D3C CD3
O
Another Equilibrium: Reaction At The α-Position
Halogenation At The α-Position
Me Me
O Br2, H2O
Me CH2Br
O
Me Me
O I2, H2O
Me CH2I
O
Me Me
O Cl2, H2O
Me CH2Cl
O
Arthur Lapworth, in 1904, discovered that the above reactions have exactly the same rates and are 1st order in acetone but zero order in halide!
Me Me
O Br2, H2O
Me CH2Br
O
Arthur Lapworth, in 1904, discovered that the above reactions have exactly the same rates and are 1st order in acetone but zero order in halide!
Me Me
O
Me CH2
OHslow fast
Br Br
Me CH2Br
O
+ HBr
Acid, which is produced in the reaction, is also a catalyst in the reaction. This process is therefore autocatalytic.
Rate dietermining step
This step is after the rate determining step and does not enter into the rate equation.
Halogenation At The α-Position
Carbonyls: Weak Acids At The α-Position
O
H
CH2
H
CH3
H
pKa = 15-20 pKa = 44 pKa = 60+
CH3
localized anion
CH2O
O
Reminder – alcohols have a 15-20 pKa range!
Carbonyls: Weak Acids At The α-Position
O
α
β
γ
Me Me
O –OD, D2O
D3C CD3
O
Mechanism:
Me CH2
O
H
OD
Me CH2
O
Me CH2
O
an enolateD–OD
Me CH2
O
D
repeat 6 times
D3C CD3
O
The Haloform Reaction
Me Me
O Excess Br2, –OH
Me OH
O
Mechanism:
Me CH2
O
H
OH
CH2
O
Me
enolate
formation
Br Br
Me CH2
O
Br
α-bromo ketone is now more acidic
repeat 2 times
Me CBr3
O
OH
Me CBr3
O
OHMe OH
O
CBr3 +
The Aldol Reaction
O
MeH
O
MeH
HO
CH2H
H
O
MeH
H
O
H Me
OHH
O
H Me
OH
a β-hydroxy carbonyl
enol
Mixed Aldol Reactions: Non-Enolizable Aldehydes
O
MeMe
O
MeMe
HO
CH2Me
H
O
PhH
H
O
Me Ph
OHH
O
Me Ph
OH
a β-hydroxy carbonyl
H3O+
Acidic:
Basic:O
MeMe
O
CH2Me
O
PhH O
Me Ph
O O
Me Ph
OH
a β-hydroxy carbonyl
–OH
H2O
H2O
O
MeMe
OH
CH2Me
O
Me H
OHH3O++
O
MeH
+OH
CH2H
O
MeH
H
+O
H H
OH
Mixture of Aldol Addition Products
Mixed Aldol Reactions: Enolizable Aldehydes
O
Me
O
CH2
O
H
OH+
O
Me
O
PhH
Mixture of Aldol Addition Products
Me Me Me
–OH
Less stable, less hindered More stable, more hindered
Me
O
MeMe
HO Ph
+
Aldol Reactions With Unsymmetrical Ketones
O
Me Ph
OH
a β-hydroxy carbonyl
Acidic:
Basic:
O
R Ph
OHH
H
OH2
O
R Ph
an α,β-unsaturated carbonyl
O
R Ph
OH
H
–OH
O
R Ph
an α,β-unsaturated carbonyl
H3O+ E2
E2
The Aldol Condensation
O
H
How can we make this compound from a linear precursor?
O
H
O
H H+
O
H
comes from an aldol condensation
O
H
OH
comes from an aldol addition
O
H
O
H
Linear Precursor (what is this compound called?)
OH
H
OH
H
OH
H
OH
O
H
OH2
"irreversible" stepO
H HH2O
O
H
How can we make this compound from a linear precursor?
Irreversible Enolate Formation: A "Better" Base
Me
O
Me
Me
Me
O
Me
Me
pKa = 15-20
pKa = 35
LDA
only enolate formed
HNMe Me
Me Me
diisopropyl amine
NMe Me
Me Me
Li
BuLi
Lithium Diisopropyl Amide
• LDA is very hindered – it will not add to carbonyl groups as a nucleophile
• Enolate formation is kinetically controlled and irreversible.
(LDA)
O
Me Me
LDA O
Me CH2
D2O Br2
MeIO
Me CH2
Me
O
Me CH2
Br
O
Me CH2
D
Li
O
R H
O
Me R
OH
Reactions of Enolates
Enol and Enolate Formation:Stereoelectronic Restrictions
An anion can only be resonance stabilized if the orbitals are aligned:
O
Hσ C–H
π* C–O
O
π* C–O
base
CLP
HO
Me Me
O
H HH H
pKa > 60, no overlap between CLP and π* C–O
O
π* C–OCLPAll 4 α-hydrogens are equivalent (pKa = 19)
base
Me
Me
Me
Me
Enol Equilibria of Carbonyl Compounds
Me Me
O
Me CH2
OHH2O
the keto form the enol form
Keq = 6 X 10-9
Me
O H2O
the keto form the enol form
Me
O
Me
OH
Me
OKeq = 4.0
O
Does this compound exist? Why or why not?
Enol and Enolate Formation:Stereoelectronic Restrictions
O
MeEt
MeMeMe
baseWhat enolate is formed?
O
MeEt
MeMeMe
base
Met-BuEt
O
Ha
Hb
good overlap with π* C–O
no overlap with π* C–O
t-Bu group "anchors" this chair conformation
Ha
Mering
Oring
OringHb
ring
Et
O
MeEt
MeMeMe
Enol and Enolate Formation:Stereoelectronic Restrictions
O
Me
Me
MeMgCl
OH
Me
Me
Me
O
Me
Me
O
Me
Me Me
Me2CuLi
O
Me
Me
OH
Me ?
Aldol-Type Reactions with Conjugated Acceptors:The Michael Reaction
Aldol-Type Reactions with Conjugated Acceptors:The Michael Reaction
O
Me
Me
OH
Me
1
23
4
O
Me
Me
OH
Me
1
23
4
Me
1
23
4
HO Me O
MeThe 1,2-addition product
OH
Me
Me
1
23
4
OMe
O
Me
Me
1
23
4
OMe
The 1,4-addition product
Thermodynamically Favored Observed Product
Tandem Aldol and Michael Reactions:The Robinson Annulation
O
H3O+ OMe
O
Basic Disproportionation of Non-Enolizable Aldehydes:The Cannizaro Reaction
H
O
MeKOH
H2OAldol reaction products
H
O
KOH
H2OHO
O
HO+
50% 50%
The Aldol Reaction
OMe
X
MH R
OO
XMe
R
OHOMe
X
base* *
• Forms a Carbon-Carbon bond, generates a β-hydroxy carbonyl compound
• Creates 2 stereocenters
Erythromycin Seco Acid
Retro-biosynthesis
Erythromycin A
Erythromycin Seco Acid – 7 Propionate Subunits
✻✻✻✻– CO2
ReductionAcylation
Polypropionate Biosynthesis: The Elementary Steps
ReductionAcylation– CO2
H
HNMe2
OH
Me
O
MeOMe
O
Me
OH
O
O
OHHOMe
Me Me
OH Me
O
OEtMe
OMe
OH
MeO
MeOEt
O
MeOH
OH
MeMe
MeHO OH HH
Me
Me Me
OH
OH Me
O
OEtMe
OMe
OH MeOH
OH
Me
OH
Me
O
Me Me
OH
Me
OH
Me
O
O
Me
OH
Me
OOH
MeMe
O
Me
OH OH
Me
OH
OH
OHOOHOH
OHMe
R
O
Me
O
Me
OHO
SRR SR R SR
O
SR
OH
Me
OH
Me
O
RMe
O
R SR
OH
Me
O
The Aldol Reaction in BiologyThe Aldol Reaction in Biology
