Further Organic Chemistry

Lecture 5 Carbonyl Chemistry

for the Michael Addition
Ying Li
NUIST
Revisiting Points
• Enolates are good nucleophiles
• Enolates are originated from carbonyl compounds
• aldehydes/ketones, esters, dicarbonyl compounds, etc

O O
E+
E

• The electrophile we have encountered

• alkylating agents
• carbonyl species
• aldehydes/ketones (Aldol , Stobbe)
• esters (Claisen, Dieckmann)
• acyl halides and acetic anhydrides 2
Unsaturated Carbonyl Compounds
• Isolated unsaturated carbonyl compounds
• the double bond(s) does not influence the electron distribution of the carbonyl group
• carbonyl group can still be the reaction hot spot for nucleophilic addition (as an electrophile)
• the chemistry is similar as individual carbonyl and double bonds
O

n
n=1,2,3...
• Conjugated unsaturated carbonyl compounds
• π-electrons are delocalized
• The carbonyl carbon is no longer the single electrophilic atom

δ-
O
O O δ+ 3
δ+
Conjugated Unsaturated Carbonyl Compounds
• often called α,β-unsaturated carbonyl compounds

δ-
O Nu
δ+
Nu
δ+
1,4-addition 1,2-addition
Conjugate addition

O O
Nu
Nu

4
Conjugated Unsaturated Carbonyl Compounds
• How to determine if the reaction is 1,4-addition or 1,2-addition?
• What determines how a reaction proceeds?
• activation energy ΔG≠
• overall reaction enthalpy (ΔH) and entropy (ΔS) [overall reaction free Gibbs energy ΔG]

Kinetic control
or
Thermodynamic control
ΔG1≠ ΔG ≠2

ΔG1 Reactant ΔG2

Product 1 Product 2
5
Conjugated Unsaturated Carbonyl Compounds
δ-
O Nu
δ+
Nu
δ+
relatively a weaker nucleophile relatively a better nucleophile
higher activation energy lower activation energy

Thermodynamic Kinetic
control
O O control
Nu
Nu
enolate is stabilized by resonance
more stable in energy No additional stabilization effect

• Conjugate addition is thermodynamically controlled

• 1,2-addition is kinetically controlled 6
Conjugated Unsaturated Carbonyl Compounds
• 1,2-addition (direct addition)
• Kinetic control
• Usually require a more reactive nucleophile
• Grignard reagents, organolithium reagents

O O MgBr OH
H3O+
+ CH3MgBr
CH3 CH3

O Li OH
O H3O+
+ BuLi
Bu Bu

7
Conjugated Unsaturated Carbonyl Compounds
• 1,4-addition (also called conjugate addition)
• the corresponding 1,2-addition is reversible (low activation energy and less stable product)

O
conjugate O Aldol
O O O
O addition
+

H3O+

O O

OH O

8
Conjugated Unsaturated Carbonyl Compounds
• 1,4-addition (conjugate addition)
• Nucleophilic addition of carbanion or other nucleophile to the α,β-unsaturated carbonyl
compounds
• Usually called as Michael addition

Nucleophile Electrophile R
R B
R'
+
R' R'' R''
Michael donor Michael acceptor

R, R'= electron withdrawing groups as carbonyl, cyano...

R''= carbonyl (mostly) or nitro
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Michael Addition

Arthur Michael (1887)

Ph Ph
NaOEt CO2Et
EtO2C CO2Et +
CO2Et EtOH EtO2C CO2Et

Diethyl malonate Ethyl cinnamate

Arthur Michael (1894)

CO2Et
Ph
EtO2C CO2Et + NaOEt H
Ph CO2Et
EtOH
EtO2C CO2Et 10
Diethyl malonate Ethyl phenylpropynoate
Michael Addition
• Stabilized enolates are good Michael donors
• α-diesters, β-keto esters, or β-diketones are excellent Michael donors
• can form stable enolate anions
• the product can easily be converted to functionalized products
O O
O
O NaOEt EtO OEt
EtO OEt EtOH OEt 1. NaOH, H2O OH
+ OEt
EtO OH
O O O 2. HCl, Δ
O
EtO O O
HO O

O O
O NaOEt
EtO OEt EtOH EtO OEt
+ OEt
O O EtO O
O
HCl, H2O, Δ OH Ac2O 11
Δ
HO O O O O
Michael Addition
• Only catalytic amount of base is required
• the proton exchange determines the catalytic cycle
• This also favors the thermodynamic control
CO2Et
O O

R2 OR1

CO2Et CO2Et H ii
O O
O O
R2 OR1 H
R2 i OR1
pKa-i 13~18
H
pKa-ii 20~25CO2Et
R2
EtO2C O
12
O
R2

pKa 10~15
Practice
• Determine the product of the following reaction and identify the roles of the reagents
other than the starting materials

O O O KOH (cat)
+ BnEt3NCl (cat)
Ph Ph

13
Michael Addition
• Enols are more likely than enolates to undergo Michael addition
• reactions take place under acidic conditions
• β-dicarbonyl compounds are enolized to a significant extent under acidic conditions

O O O
O AcOH, H2O
+ Δ
O O

14
Michael Addition
• Enamines, as the convenient stable enol equivalents, are good Michael donors

O O
N O N O
+ H3O+, Δ OH
OH OH

15
Practice
• Provide products for the following reactions. Propose reasonable mechanisms for them.

O
O H2O
+ H

O
N H3O+, Δ
OMe
+
SMe

O
O
N H3O+, Δ
+
SO2Ph 16
Michael Addition
• α,β-unsaturated carbonyls are good Michael acceptors

• α,β-unsaturated nitriles are ideal for Michael addition

+ Nu Nu
Nu C C C
N N N

O
O NaOEt
+ CN NC
Ph
Ph

17
Practice
• Design synthetic route to complete the following conversion

NC
HO2C NH2
HO2C NH2

18
Michael Addition
• 1-Nitroalkene is also a good Michael acceptor

• Nitro is a much stronger EWG than carbonyl

O O
O O NaOEt, EtOH
+ O2N OEt
OEt
O2N

19
Practice
• Determine the product of the following reaction and state your reason

O
1. EtO2C
N NO2
2. H3O+, Δ

20