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Organic Chemistry, Third Edition
Chapter 24 Carbonyl condensations
2
Review: enolates
enolates = nucleophiles
React with electrophiles as in SN2 reactions with alkyl halides
OLDA, -78 °C
THF
O RX
R = Me, 1° alkyl
OR
O
THF, RT
O RX
R = Me, 1° alkyl
ONaH
R
kinetic
thermodynamic
3
O
H
H
O
HpKa 19 pKa 17
RO
O
H
R2N
O
H
RO
O
H
O
OR RO
O
H
O O
H
O
pKa 24 pKa 33
pKa 15 pKa 13 pKa 9
P CH3Ph
PhPh
pKa 22
N
O
HpKa 15 (in water)pKa 23 (in org)
NH
O
OpKa 15 (in org)
ONH
O
pKa 21 (in org)
NH
O
pKa 24 (in org)
HO
O
pKa 4.76
OH
pKa 10
OH
pKa 16
HOH
pKa 15.7
H3O+
pKa -1.7
HCl
pKa -8
H2SO4
pKa -3 & 2
pKa’s
Review: enolates
OLDA, -78 °C
THF
OO
R'Br O
O
R'
O
BuOH
O OtBuOK
O
OEtBr
O
OEt
React with alpha halo ketone, aldehydes and esters 1,4-dicarbonyls
Reaction of enolates with other electrophiles: cyclic ethers
reaction with: epoxide (oxirane) = γ hydroxy-ketone oxacyclobutane (oxetane) = δ hydroxy-ketone
OLDA, -78 °C
THF
O OO
HO2) aq. acid
1)
OLDA, -78 °C
THF
O O
2) aq. acid
1) O
HO
6 6
Condensation Reactions Between Two Carbonyl Compounds
(Adol)
R'
OR R'
OR
R"
XO R'
O
R
R" X
O
R'
O
R
R" X
O
X = Cl, OR
R'
O
R
R"
O 1,3-dicarbonyl
R'
O
R
R" X
O
X = alkyl or aryl or alkenyl
-X
R'
O
R
R" X
OH R'
O
RR"
X
-OHHOH
X = alkyl or aryl or alkenyl
7
• In the aldol reaction, two molecules of an aldehyde or ketone react with each other in the presence of a base to form a β-hydroxy carbonyl compound.
The Aldol Reaction
acetaldehydeO
HH
H H
NaOEt
EtOH
O
HH H
OH
HH
H
H
3-hydroxybutanal
e.g.
R'
O
R
R'
OR'
OR
R'
OR
R' = H, alkyl, aryl
Base
HH H-BaseH
R'O
RHH
R
R'
O
R
R'
OH
R
β-hydroxy ketone
HOH
With RO- as base, thermodynamic process
8
Adol Mechanism with aldehydes
O
HH
H H
EtO
O
H
H
H
OH
HH
HO
H
H
H
O
HH
H
O
H
HH
H
H O Et
O
HHH
OH
HH
H
H
formation of enolate
nucleophilic addition
EtOH
pKa 17pKa 16
Equilibrium reaction (reversible) Aldehyde equilibrium favors products
nucleophile
electrophile
9
Adol Mechanism with ketones
Equilibrium reaction (reversible) Ketone equilibrium favors starting materials Lower acidity of ketone (pKa 19) compared with aldehyde (pKa 17)
nucleophile
electrophile
O NaOEt
EtOH
O O
O
O
pKa 19
+ EtOH
pKa 16
O O O OH
10
Retro-Aldol Reaction (ketones)
O O O OH
OEt
O O
H O Et
O2
11
Retro-Aldol Reaction (ketones) in Nature: Glycolysis of sugars (part of making ATP)
CHOOHHHHOOHHOHH
CH2OH
CHOOHHHHOOHHOHH
CH2O PO
OO
ATP ADPkinase
CH2OHOHHOOHHOHH
CH2O PO
OO
ATP ADPCH2O
OHHOOHHOHH
CH2O PO
OO
PO
O
O
CH2OOHHOOHHOHH
CH2O PO
OO
PO
O
O
aldolase
OH
OHHCH2O P
O
OO
CH2OO
HHO
PO
O
O
H
dihydroxyacetone phosphate
glceraldehyde phosphate
O
O
O-2
+ 4 ATP
Adol Condensation Refers to an Adol reaction followed by dehydration (E1CB) to an α,β-unsaturated aldehyde or ketone.
ketones will undergo aldol condensations in high yield
H
O NaOEt
EtOHH
O
H
O
H
O HO
pKa 17
+ EtOH
pKa 16
H
O O
HH
O OH
H
H
O OH
H
Heat
H
OEt
-OH-H
O
α,β-unsaturated aldehyde
enone
H
H
O OH
H
E1cB
Adol Condensation of ketons Adol reaction of ketone is not favorable. Adol condensation is favorable.
E1CB = Elimination Unimolecular conjugate base
O NaOEt
EtOH
O O
O
O
pKa 19
+ EtOH
pKa 16
O O O OH
O OH Heat
H
OEt
-OH-
O
α,β-unsaturated aldehyde
enone
O OH
E1cB
Adol Condensation Even more favored by: aromatic groups or other extended conjugation
ketones will undergo aldol condensations in high yield
ONaOEt
EtOHOOHO
Acid catalyzed Adol Condensation
generally leads to elimination (not E1cB)
O acidO
OH
A
OH
H
OH
OOH
H
O
OH
A
O
OH
HA
O
OH
H
H
A
O
Acid catalyzed Adol Condensation
What is wrong with this mechanism???
OH
A
OH
H
OH
OO
H
H
O
OH
O
OHH
A
O+ OH
Hydroxide is a strong base. Can’t have in presence of acid
17
• To utilize the aldol reaction in synthesis, you must be able to determine which aldehyde or ketone is needed to prepare a particular β-hydroxy carbonyl compound or α,β-unsaturated carbonyl compound—that is, you must be able to work backwards in the retrosynthetic direction.
Retrosynthetic Analysis of Aldol Products
18
Retrosynthetic Analysis of Aldol Products
Identifying adol and adol condensation products adol reaction: beta hydroxy groups to aldehyde or ketone carbonyl adol condensation: enone
O OH O OH O O
Identifying adol and adol condensation products adol reaction: beta hydroxy groups to aldehyde or ketone carbonyl adol condensation: enone
O
OH
O
OH
O
O
Identifying adol and adol condensation products adol reaction: beta hydroxy groups to aldehyde or ketone carbonyl adol condensation: enone
O OOH OO
Crossed aldols
Problem: No selectivity, mixtures of products Solution: aldehyde without alpha protons
O
H
O
H O
H
HO
O
H
HO
O
H
HO
O
H
HO
A
B A + B A + A B + AB + B
NaOH
O
H
O
H O
H
O
H
O
HO
HA
B A + B A + A B + AB + B
NaOH
Heat
Adol reaction
Aldol condensations
Crossed aldols
Problem: No selectivity, mixtures of products Solution: aldehyde without alpha protons
O
H
O
H
NaOH
O
H
Better Solution: Directed adol. Make enolate qunatitatively in one step. Then add it slowly to excess of second carbonyl (electrophile).
O
H
NaH
THF
O
H
O
H
O
H
HOacid or base
heatO
H
24
• A directed aldol reaction is one that clearly defines which carbonyl compound becomes the nucleophilic enolate and which reacts at the electrophilic carbonyl carbon:
[1] The enolate of one carbonyl component is prepared with LDA.
[2] The second carbonyl compound (the electrophile) is added to this enolate.
• Both carbonyl components can have α hydrogens because only one enolate is prepared with LDA.
• When an unsymmetrical ketone is used, LDA selectively forms the less substituted kinetic enolate.
Directed Aldol Reactions
Crossed aldols
H H
OO
NaH
THF
O O
2) aqueous acid
OH
heat
or1) TsCl,pyridine2) tBuOK
O
26
• The aldol reaction is synthetically useful because it forms new carbon–carbon bonds, generating products with two functional groups.
• β-Hydroxy carbonyl compounds formed in aldol reactions are readily transformed into a variety of other compounds.
Figure 24.3 Conversion of a β-hydroxy
carbonyl compound into other compounds
Useful Transformations of Aldol Products
27
[2] When one carbonyl component has especially acidic α hydrogens, these hydrogens are more readily removed than the other α H atoms. • As a result, the β-dicarbonyl compound always becomes
the enolate component of the aldol reaction.
Use of Crossed Aldol Reactions
28
• β-Dicarbonyl compounds are sometimes called active methylene compounds because they are more reactive towards base than other carbonyl compounds.
• 1,3-Dinitriles and α-cyano carbonyl compounds are also active methylene compounds.
Active Methylene Compounds
29
• In this type of crossed aldol reaction, the initial β-hydroxy compound always loses water to form the highly conjugated product.
Figure 24.2 Crossed aldol reaction
between benzaldehyde and diethyl malonate
Example of Crossed Aldol Reactions
Adol condensation reaction in biochemistry: tough meat
• Meat of older animals is tougher than that from young animals • Toughening is due to cross-linking between collagen protein macromolecules
HN N
H
HN
O
O
O
NH HN
HNHN
O
O
ONH
OO
O
NH2
Oxidative deamination
HN N
H
HN
O
O
O
NH HN
HNHN
O
O
ONH
OO
O
O
H
Adol Condensartion
HN
NH
HN
O
O
O
NH HN
HNHN
O
O
ONH
OO
O
OH
HN
NH
HN
O
OO
NH
NHNH HNO
OO
NH
O
OO
H
31
Directed Aldol Reactions • Periplanone B is an extremely active compound produced in
small amounts by the American cockroach. • Its structure was determined using 200 µg isolated from more
than 75,000 female cockroaches.
Figure 24.4 A directed aldol reaction
in the synthesis of periplanone B
1,2 addition to aldehyde 1,4 to vinyl ketone
32
• Aldol reactions with dicarbonyl compounds can be used to make five- and six-membered rings.
• The enolate formed from one carbonyl group is the nucleophile, and the carbonyl carbon of the other is the electrophile.
• For example, treatment of 2,5-hexadienone with base forms a five-membered ring.
• 2,5-Hexanedione is called a 1,4-dicarbonyl compound to emphasize the relative positions of its carbonyl groups.
• 1,4-Dicarbonyl compounds are starting materials for synthesizing five-membered rings.
Intramolecular Aldol Reactions
33
34
• When 2,5-hexanedione is treated with base in Step [1], two different enolates are possible—enolates A and B, formed by removal of Ha and Hb, respectively.
• Although enolate A goes on to form the five-membered ring, intramolecular cyclization using enolate B would lead to a strained three-membered ring.
Use of Crossed Aldol Reactions
• Because the three-membered ring is much higher in energy than the enolate starting material, equilibrium greatly favors the starting materials and the three-membered ring does not form.
35
• In a similar fashion, six-membered rings can be formed from the intramolecular aldol reaction of 1,5-dicarbonyl compounds.
Intramolecular Aldol Reactions
36
• The synthesis of the female sex hormone progesterone involves an intramolecular aldol reaction.
Figure 24.5
Synthesis of Progesterone Using an Intramolecular Aldol Reactions
37
• In the Claisen reaction, two molecules of an ester react with each other in the presence of an alkoxide base to form a β-keto ester.
• Unlike the aldol reaction which is base-catalyzed, a full equivalent of base is needed to deprotonate the β-keto ester formed in Step [3] of the Claisen reaction.
• Since esters have a leaving group on the carbonyl carbon, loss of the leaving group occurs to form the product of substitution, not addition.
The Claisen Reactions
38
39
• The characteristic reaction of esters is nucleophilic substitution.
• A Claisen reaction is a nucleophilic substitution in which an enolate is the nucleophile.
Figure 24.6
Claisen Reaction—Example of Nucleophilic Substitution
Claisen condensation reaction in biochemistry: Fatty acid synthesis
SCoA
O+ ACP
SACP
O
SCoA
OO
O+ ACP SACP
OO
O
SACP
OOHSACP CO2
NADPH + H+ NADP+
SACP
OOH
SACP
OOH
SACP
ONADPH + H+ NADP+
SACP
O
CoA:ACP transacylase
3-ketoacyl-ACP synthetase
!3-ketoacyl-ACP reductase
CoA:ACP transacylase
3-Hydroxyacyl ACP dehydrase
!Enoyl-ACP reductase
Fatty acid
S
ONH
O
NH
O
PO
OOH
PO OH
O
HOOO
HON N
NN
NH2
PO
HOHO
N
NN
N
NH2
O
OOH
HH
HH
O
POO-
O-
O
P O-O
O
P
-O
O ON
NH2
O
OHHO
NADP
N
NN
N
NH2
O
OOH
HH
HH
O
POO-
O-
O
P O-O
O
P
-O
O ON
NH2
O
OHHO
NADPH H H
42
polyketide metabolites
43
44
• Like the aldol reaction, it is sometimes possible to carry out a Claisen reaction with two different carbonyl components as starting materials.
• A Claisen reaction between two different carbonyl compounds is called a crossed Claisen reaction.
• A crossed Claisen is synthetically useful in two different instances: [1] Between two different esters when only one has
α hydrogens, one product is usually formed.
Crossed Claisen Reaction
45
Crossed Claisen: Side reaction
ethyl 3-oxo-3-phenylpropanoate
ethyl acetoacetate
OEt
O O
OEt
O
OEt
O
OEt
O
OEt
OOEt
O O
bp 212 °C
bp 77 °Cbp 180 °C
bp 265 °C
How should reaction be set up?
46
[2] Between a ketone and an ester—the enolate is always formed from the ketone component, and the reaction works best when the ester has no α hydrogens.
• The product of this crossed Claisen reaction is a β-dicarbonyl compound, not a β-keto ester.
Crossed Claisen Reaction
Vast excess of ethyl formate (low bp)
47
• β-Dicarbonyl compounds are also prepared by reacting an enolate with ethyl chloroformate or diethyl carbonate.
Forming β-Dicarbonyl Compounds
Ethyl chloroformate reacts with ethoxide to form diethyl carbonate
48
• Reaction [2] is noteworthy because it provides easy access to β-keto esters, which are useful starting materials in the acetoacetic ester synthesis.
• In this reaction, Cl− is eliminated rather than −OEt in Step [3] because Cl− is a better leaving group, as shown in the following steps.
Preparing β-Keto Esters
49
• An intramolecular Claisen reaction is called a Dieckmann reaction.
• Two types of diesters give good yields of cyclic products.
The Dieckmann Reaction
50
The Michael Reaction
O
OEt
OO+ 1) NaOEt, EtOH
2) H3O+, heat
O O
1,5 dicarbonyl
Acid catalyzed decarboxylation removes one of CO2R
RO2C CO2RRO2C CO2R
pKa 12EWG
RO2C CO2R
EWGH OR
ROH
RO-
RO2C CO2R
EWG
HRO-
RO2C CO2R
EWG
H+, H2O
Δ
HO2C
EWG
52
• The Michael reaction involves two carbonyl components—the enolate of one carbonyl compound and an α,β-unsaturated carbonyl compound.
• Recall that α,β-unsaturated carbonyl compounds are resonance stabilized and have two electrophilic sites—the carbonyl carbon and the β carbon.
The Michael Reaction
53
• The α,β-unsaturated carbonyl component is often called a Michael acceptor.
Michael Acceptors
54
55
• When the product of a Michael reaction is also a β-keto ester, it can be hydrolyzed and decarboxylated by heating in aqueous acid.
• This forms a 1,5-dicarbonyl compound. • 1,5-dicarbonyl compounds are starting materials for
intramolecular aldol reactions.
Michael Reaction Products
56
Figure 24.7 Using a Michael reaction in the synthesis of the steroid estrone
Using the Michael Reaction
57
Broader interpretation of Michael reaction: include enamines, amines and enolates as nucleophiles (Michael donors)
O O
OR
O
NR'2
NO2 CN
EWG
Michael Acceptors
EWG EWG
EWG
EWG
EWGO
Hacrolein (often enolates add 1,2)
Michael Donors
RO2C CO2R RO2C COR ROC COR NC CN O2N NO2
N OO2N RNH2
58
Recognizing Michael Adducts (Reaction Products)
O2N
O
O2N
O
O2N
O
59
Recognizing Michael Adducts (Reaction Products)
O O
OEt
O O
OEt
O O
OEt
60
Michael additions in Nature
SS
S
O
HN
O
O
Osugar
Reduction
S
O
HN
O
O
Osugar
Michael Add
OHN
O
O
Osugar
S
OHN
O
O
Osugar
S
Bergman rearrangement
Diradical
Calicheamicin
Calicheamicins target DNA, causing strand scission.
Drug for non-solid tumor cancer acute myeloid leukemiaOne of the most potent anti-tumor agents known.
61
• The Robinson annulation is a ring-forming reaction that combines a Michael reaction with an intramolecular aldol reaction.
• The starting materials for a Robinson annulation are an α,β-unsaturated carbonyl compound and an enolate.
The Robinson Annulation
62
• The Robinson annulation forms a six-membered ring and three new C–C bonds—two σ bonds and one π bond.
• The product contains an α,β-unsaturated ketone in a cyclohexane ring—that is, a 2-cyclohexenone.
• To generate the enolate component of the Robinson annulation, −OH in H2O or −OEt in EtOH are typically used.
The Robinson Annulation
63
64
65
• To draw the product of Robinson annulation without writing out the entire mechanism each time:
[1] Place the α carbon of the carbonyl compound that becomes the enolate next to the β carbon of the α,β-unsaturated carbonyl compound.
[2] Join the appropriate carbons together as shown. If you follow this method of drawing the starting materials, the double bond in the product always ends up in the same position of the six-membered ring.
Drawing Products of Robinson Annulation
66
67
Synthesis Using the Robinson Annulation
68
Reactions Adol
O
HNaOEt
EtOH
O
H
OHNaOEtHeat
O
H
O O NaOEt
EtOH
OIntramolecular Adol
Directed Aldol
O1) LDA, THF, -78 °C
2) CH3CHO3) aq. work-up
O
OH
1) LDA, THF, -78 °C
2)Cl
O
HO
O
1) NaH, THF
2)EtO
O
OEt
O O
OEt
OO
EtO OEt
CHO
NaOEt
EtOH
CO2Et
CO2Et+
69
Reactions
O
OEtNaOEt
EtOH
O
OEt
O
Claisen
OEt
ONaOEt
EtOHO
EtOO
O
OEtDiekmann
Michael Addition
O
OEt
O NaOEt, EtOH
O
O
OEt
O
O
Robinson Annulation
O
O
O
1,5 dicarbonyl
Michael addition then intramolecular adol
70
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