Transcript Ch. 18 Lect. 2 Complex Carbonyl Reactions I. Aldol Condensation

Ch. 18 Lect. 2 Complex Carbonyl Reactions
I.
Aldol Condensation
A.
Two aldehyde molecules can react to form an a,b-unsaturated aldehyde product
1) This reaction allow C—C bond formation between 2 carbonyl compounds
2) It is base catalyzed
3) Condensation = when 2 molecules combine and give off H2O
O
H
C
O
+
CH3
H
acetaldehyde
C
OH-, H2O
CH3
5 oC
OH
H3C
CH
O
O
CH2 C
3-hydroxybutanal
H
H

C
C
H3C
C
H
H
a,b-unsaturated aldehyde
trans-2-butenal
4)
This reaction works for all aldehydes and some ketones
5)
Mechanism
a) Enolate formation is the initial step
b) Nucleophilic carbon of the enolate attacks the carbonyl of the second
aldehyde
H OH
O
O
H
C
O
OHCH2
H
H
C
H
C
O
CH3
H
CH2
O
H
C
C
O
H
H
B.
CH3
CH2
C
CH3
Aldol
The reaction can be stopped at this point at low temperature
At higher temperature, dehydration follows
OH
CH
OH
H
Enolate
small concentration
c)
d)
C
-
OH
H
C
O
OH
CH
C
H
CH3
-H2O
C
CH CH CH3
H
a,b-unsaturated aldehyde
Using the Aldol Condensation
1) C—C bond formation is always important for synthesis
2) This is the first example of carbonyl—carbonyl addition
3) Product functional groups are flexible depending on temperature
4)
O
CH3CHCH
CH3
Low temperature example:
O
OH-, H2O
CH3CHCH
+
5 oC
CH3
CH3
CH3CH
OH
CH3
O
C
C
CH
H
CH3
Aldol
5)
High temperature example
b H
H
K2CO3, H2O, 
O
H
O
C.
H
a
O
a,b-unsaturated aldehyde
Ketones can undergo Aldol Condensation
1) Aldehyde carbonyls are not stabilized very much by single R group, so the
Aldol Condensation is exothermic (more stable product)
2)
Ketone Carbonyls are more stable; the Aldol condensation is generally
endothermic
O
O
H3C
H3C
C
CH3
OH
CH3
OH
C CH3

-H2O
Aldol 6%
H3C
O
C
CH
C CH3
H3C
a,b-unsaturated ketone 80%
We can force the reaction towards completion by removing product or H2O
Crossed Aldol Condensation
1) Reaction of two different aldehydes or ketones is called Crossed Aldol
2) Crossed Aldol Condensations gives product mixtures
C
OH
H3C
H
+
NaOH
O
CH3CH2
CH2
CH3
O
H3C
O
H3C C
-
3)
D.
C
C
O
C
CH
H
CH3
OH
H
+ H3C
CH
C
OH
H
CH3CH2
+
CH2 C
OH
O
CH2 C
CH
O
H
+
CH3CH2
CH
H
O
CH C
CH3
H
2)
Crossed Aldol Condensations are only selective if one carbonyl has no a-H’s
CH3 O
H3C
C
CH3
C
O
+
H CH3CH2
C
CH3 OH
H
NaOH
H3C
C
C
CH3 H
O
CH
C
H
CH3
-H2O
CH3
H3C
C
O
C
CH3 H
E.
CH3
Intramolecular Aldol Condensations give cyclic products
1) Low concentrations ( < 0.001 M) of the linear molecule are used to prevent
intermolecular interactions = High Dilution Reaction
O
O
C CH
O
HCCH2CH2CH2CH2CH
NaOH
O
C H
-H2O
H
H OH
C H
H
2)
5- and 6-membered rings are most favored due to low ring strain
O
O
O
NaOH
H3C
O
OH
-H2O
+
H3CCCH2CH2CCH3
O
0%
3)
II.
H3C OH
H3C
CH3
100%
Intramolecular Ketone Aldol Condensations are more likely than the
intermolecular reaction
a) G = H – TS is endothermic for ketone aldol condensation partly
due to unfavorable entropy (2 particles  1 particle)
b) The Intramolecular reaction is less endothermic because entropy
does not disfavor a 1 particle  1 particle reaction
Other routes to a,b-Unsaturated Aldehydes and Ketones
A.
Base mediated Dehydrohalogenation
O
O
Cl2, CCl4
O
E2
Cl
H
OH-
B.
Wittig Reaction
1) Carbonyl Substituted Ylides are stabilized by resonance
O
O
(C6H5)3P
(C6H5)3P
CH CH
2)
(C6H5)3P
O
CH CH
(C6H5)3P
CH
CH
These stable Ylides will react with Aldehydes to give a,b-Unsaturated
aldehydes
O
CH CH
H
+
O
O
C.
H
Oxidation of Allylic Alcohols by MnO2
O
H2C CH
CH2OH
MnO2
H2C CH
CH
III. Properties of a,b-Unsaturated Aldehydes and Ketones
A.
a,b-Unsaturated Aldehydes and Ketones (also known as Enones) are
difunctional: alkene and a carbonyl
1) Sometimes they react at a single functional group in normal alkene or
carbonyl reactions
2) Sometimes the reactivity is over the whole enone functional group
B.
Conjugated Enones are Stabilized
1) Resonance forms of conjugated enone 2-butenal
O
O
H3C CH
CH
2)
H3C CH
CH
CH
CH
O
H3C CH
CH
CH
“Moving Into Conjugation” of nonconjugated enones
a) Isomerization to a more stable form can occur in basic conditions
b)
Example:
O
H2C CH
CH2
not conjugated
CH
O
-
OH
H2O
H3C CH CH
conjugated
CH
c)
Mechanism
O
H2C CH
O
H2C
CH
CH2
CH
CH
CH
O
O
OHH2O
H2O
H2C CH
CH
CH
H3C CH
+ OH-
O
H2C
C.
CH
CH
CH
Enone reactions are often typical of alkene and carbonyl chemistry
1) Alkene Hydrogenation
H2, Pd/C
O
2)
O
Electrophilic Addition to C=C p system
O
CH3CH=CHCCH3
O
Br2, CCl4
CH3CHCHCCH3
Br Br
CH
CH
3)
Conjugate Reduction
a) Selective for conjugated C=C in presence of other C=C bonds
b) Similar mechanism to alkyne  trans-alkene
CH3
CH3
O
C
CH3
CH2
1. Li, NH3 (l)
2. NH4Cl, H2O
O
CH3
4)
H
C
CH3
Addition Reactions to the Carbonyl
CH2
CH3
OH
O
N
CH=CHCCH3
CH=CHCCH3
NH2OH, H+
-H2O
oxime
IV. Addition to a,b-Unsaturated Aldehydes and Ketones
A.
1,4 Additions are to the entire Enone functional group
1) 1,2 Additions to either alkene or carbonyl are just like single group cases
A
O
C
CH
C
O
O
A
B
C
CH
B
A
C
or
C
CH
C
B
2)
1,4 Additions are similar to those of 1,4-butadiene; they involve both of
the functional groups = Conjugate Addition
1) Nu- part adds to the b-carbon
2) E+ part adds to the carbonyl oxygen
3) Initial product is an enol if the electrophile is H+
4) Tautomerization then leads to a ketone product
5) The result looks like a 1,2 addition to the C=C bond
O
C
CH
C
O
Nu
H
C
CH
H
O
C
C
C
H
Oxygen and Nitrogen Nucleophile Conjugate Additions
1) ROH, HOH, RNH2 all react similarly with enones
CH
C CH3
O
H
O
H
C
Nu H
Nu
B.
CH
H2O
H C
OH
CH
H
C CH3
O
H
H C
CH
OH H
C CH3
2)
Why do the reactions go 1,4 instead of 1,2 ?
a) Both types of additions are reversible
b)
The carbonyl products of 1,4 addition are generally more stable than
the hydrate, hemiacetal, and hemiaminal products of 1,2 addition to
the carbonyl
c)
Exceptions: hydroxylamines, semicarbazides, and hydrazines lead to
precipitates that drive the 1,2 addition
O
O
3)
C.
HCN also adds 1,4 to enones
CH3CCH=CH2
HCN
Organometallic Reagent Additions to Enones
1) Organolithium Reagents add 1,2 at the carbonyl
H
O
CH3CCH=CH2
O
1. CH3Li, Et2O
+
2. H , H2O
CH3CCH=CH2
CH3
CH3CCH2CN
2)
Organocuprate reagents add 1,4 to enones
O
1. (CH3)2CuLi, Et2O
CH3CCH=CH2
3)
+
2. H , H2O
O
CH3CCH
H
CH3
The organocuprate intermediate is an enolate capable of attacking another
electrophilic carbon. This results in two alkylations of the C=C bond.
O
CH3CCH=CH2
O
1. (CH3)2CuLi, Et2O
2. CH3CH2Br
CH3CCH
CH3CH2
D.
CH2
CH2
CH3
The Michael Addition
1) Enolate Ions are good nucleophiles that can perform conjugate (1,4)
addition on enones
2) The most reactive enolates are derived from a b-dicarbonyl
O
O
CH3CCH2CCH3 +
O
pyridine
CH3C
O
CH
H2C=CHCH
CH3C
O
O
CH2CH2CH
3)
Other enolates can do the reaction as well
O
O
CH3
- +
EtO K , EtOH
H2C=CHC
+
4)
O
O
CH3
CH2CH2C
Mechanism
O
O
C
C
C
+
O
C
C C
C C
C O
O
O
O
C
C C C
C OH
a)
b)
H+
C
C
C C
a-Carbon of enolate is the Nucleophile
b-Carbon of the enone is the Electrophile
C
H
C
5)
Robinson Annulation
a) Sometimes, the Michael Addition product can undergo an
intramolecular aldol condensation
O
H3C
H
+
C
C
H
O
EtO-K+, EtOH, Et2O
Michael Addition
C CH
3
H
3-butene-2-one
H3C
O
Aldol
Condensation
CH3
CH3
, OH-
O
O
CH3
b)
+
CH2
OH
86%
54%
This sequence is called the Robinson Annulation
CH
O
O
O
-H2O
+ H2O
C
O