Carbonyl Condensation Reactions

203 Pages·2012·7.92 MB·English

24
Carbonyl Condensation Reactions
24.1 The aldol reaction
24.2 Crossed aldol reactions
24.3 Directed aldol reactions
24.4 Intramolecular aldol
reactions
24.5 The Claisen reaction
24.6 The crossed Claisen and
related reactions
24.7 The Dieckmann reaction
24.8 The Michael reaction
24.9 The Robinson annulation
Ibuprofen is the generic name for the pain reliever known by the trade names of Motrin and
Advil. Like aspirin, ibuprofen acts as an anti-infl ammatory agent by blocking the synthesis
of prostaglandins from arachidonic acid. One step in a commercial synthesis of ibuprofen
involves the reaction of a nucleophilic enolate with an electrophilic carbonyl group. In Chap-
ter 24, we learn about the carbon–carbon bond-forming reactions of enolates with carbonyl
electrophiles.
916
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24.1 The Aldol Reaction 917
In Chapter 24, we examine carbonyl condensations—that is, reactions between two car-
bonyl compounds—a second type of reaction that occurs at the α carbon of a carbonyl group.
Much of what is presented in Chapter 24 applies principles you have already learned. Many of
the reactions may look more complicated than those in previous chapters, but they are fundamen-
tally the same. Nucleophiles attack electrophilic carbonyl groups to form the products of nucleo-
philic addition or substitution, depending on the structure of the carbonyl starting material.
Every reaction in Chapter 24 forms a new carbon–carbon bond at the ` carbon to a
carbonyl group, so these reactions are extremely useful in the synthesis of complex natural
products.
24.1 The Aldol Reaction
Chapter 24 concentrates on the second general reaction of enolates—reaction with other car-
bonyl compounds. In these reactions, one carbonyl component serves as the nucleophile and
one serves as the electrophile, and a new carbon–carbon bond is formed.
Reaction of enolates with O O
other carbonyl compounds C (cid:150) + C O δ(cid:150) C α
C δ+ C C O(cid:150)
enolate second carbonyl
component new C C bond
nucleophile electrophile
The presence or absence of a leaving group on the electrophilic carbonyl carbon determines the
structure of the product. Even though they appear somewhat more complicated, these reactions
are often reminiscent of the nucleophilic addition and nucleophilic acyl substitution reactions of
Chapters 21 and 22. Four types of reactions are examined:
• Aldol reaction (Sections 24.1–24.4)
• Claisen reaction (Sections 24.5–24.7)
• Michael reaction (Section 24.8)
• Robinson annulation (Section 24.9)
24.1A General Features of the Aldol Reaction
In the aldol reaction, two molecules of an aldehyde or ketone react with each other in the pres-
ence of base to form a a-hydroxy carbonyl compound. For example, treatment of acetaldehyde
with aqueous –OH forms 3-hydroxybutanal, a a-hydroxy aldehyde.
O (cid:150)OH, H2O βOH H O a-hydroxy carbonyl
Many aldol products contain The aldol reaction 2 CH C CH C C C
3 3 compound
an aldehyde and an alcohol— H H H H
hence the name aldol.
acetaldehyde new C(cid:150)C bond
3-hydroxybutanal
The mechanism of the aldol reaction has three steps, as shown in Mechanism 24.1. Carbon–
carbon bond formation occurs in Step [2], when the nucleophilic enolate reacts with the electro-
philic carbonyl carbon.
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918 Chapter 24 Carbonyl Condensation Reactions
Mechanism 24.1 The Aldol Reaction
Step [1] Formation of a nucleophilic enolate
O [1] O O(cid:150) • In Step [1], the base removes a
H CH C (cid:150)CH C CH C + H O proton from the α carbon to form a
HO(cid:150) α 2 H 2 H 2 H 2 resonance-stabilized enolate.
resonance-stabilized enolate
Steps [2]–[3] Nucleophilic addition and protonation
H O H • In Step [2], the nucleophilic enolate
O
(cid:150) attacks the electrophilic carbonyl
C + (cid:150) O [2] O O [3] βOHα O carbon of another molecule of
CH H CH C CH C CH C CH C CH C
3 2 3 2 3 2 aldehyde, thus forming a new carbon–
H H H H H carbon bond. This joins the ` carbon
nucleophilic attack new C(cid:150)C bond + (cid:150)OH of one aldehyde to the carbonyl
carbon of a second aldehyde.
• Protonation of the alkoxide in Step [3]
forms the a-hydroxy aldehyde.
The aldol reaction is a reversible equilibrium, so the position of the equilibrium depends on the
base and the carbonyl compound. –OH is the base typically used in an aldol reaction. Recall
from Section 23.3B that only a small amount of enolate forms with –OH. In this case, that’s
appropriate because the starting aldehyde is needed to react with the enolate in the second step
of the mechanism.
Aldol reactions can be carried out with either aldehydes or ketones. With aldehydes, the
equilibrium usually favors the products, but with ketones the equilibrium favors the starting
materials. There are ways of driving this equilibrium to the right, however, so we will write aldol
products whether the substrate is an aldehyde or a ketone.
• The characteristic reaction of aldehydes and ketones is nucleophilic addition
(Section 21.7). An aldol reaction is a nucleophilic addition in which an enolate is the
nucleophile. See the comparison in Figure 24.1.
A second example of an aldol reaction is shown with propanal as starting material. The two
molecules of the aldehyde that participate in the aldol reaction react in opposite ways.
• One molecule of propanal becomes an enolate—an electron-rich nucleophile.
• One molecule of propanal serves as the electrophile because its carbonyl carbon is
electron defi cient.
Figure 24.1 O O(cid:150)
Nucleophilic addition—
The aldol reaction—An General reaction C + Nu(cid:150) CH C Nu The enolate is
3
example of nucleophilic CH3 H H the nucleophile.
addition nucleophile
(cid:150)
Aldol reaction— O O O O
An example C + (cid:150)CH C CH C CH C
2 3 2
CH H
3 H H H
• Aldehydes and ketones react by nucleophilic addition. In an aldol reaction, an enolate is the
nucleophile that adds to the carbonyl group.
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24.1 The Aldol Reaction 919
α O
H CH C
(cid:150)
HO CH H
3
propanal
H O H
(cid:150)
O O O O OH α O
C + (cid:150)CH C CH CH C CH C CH CH C CH C
3 2 3 2
CH CH H
3 2 CH H H CH H H CH H
propanal 3 3 3
electrophile nucleophile new C(cid:150)C bond
These two examples illustrate the general features of the aldol reaction. The ` carbon of one
carbonyl component becomes bonded to the carbonyl carbon of the other component.
Gerneearcatli oanldol OC + CαH2 CO (cid:150)OH, H2O RCH2 OCH CH CO
RCH H
2 R H H R H
Join these 2 C(cid:146)s together.
Problem 24.1 Draw the aldol product formed from each compound.
O
CH2CHO O
a. b. (CH ) CCH CHO c. C d.
33 2
CH CH
3 3
Problem 24.2 Which carbonyl compounds do not undergo an aldol reaction when treated with –OH in H O?
2
O
CHO O O CHO
a. b. c. C d. C e.
(CH ) C H (CH ) C CH
33 33 3
24.1B Dehydration of the Aldol Product
The β-hydroxy carbonyl compounds formed in the aldol reaction dehydrate more readily than
other alcohols. In fact, under the basic reaction conditions, the initial aldol product is often
not isolated. Instead, it loses the elements of H O from the ` and a carbons to form an
2
`,a-unsaturated carbonyl compound.
aldol dehydration conjugated product
All alcohols—including
β-hydroxy carbonyl O (cid:150)OH, H2O βOH Hα O (cid:150)OH β α O
compounds—dehydrate [1] 2 CH3 C CH3 C C C (cid:150)H O CH3CH CH C
in the presence of acid. H H H H 2 H
Only β-hydroxy carbonyl acetaldehyde β-hydroxy aldehyde α,β-unsaturated carbonyl
compounds dehydrate in the compound
presence of base.
An aldol reaction is often O HOCH3O CH3 O
α α
cbaelcleadu saen tahled oβ-l hcyodnrodxeyn sation, [2] 2 C CH3 (cid:150)OH, H2O Cβ C C (cid:150)OH Cβ C C
H H (cid:150)H O H
carbonyl compound that is 2
initially formed loses H O by acetophenone β-hydroxy ketone (E and Z isomers
2
dehydration. A condensation (not isolated) can form.)
reaction is one in which a It may or may not be possible to isolate the β-hydroxy carbonyl compound under the conditions
small molecule, in this case of the aldol reaction. When the α,β-unsaturated carbonyl compound is further conjugated with a
H O, is eliminated during a
2 carbon–carbon double bond or a benzene ring, as in the case of Reaction [2], elimination of H O
reaction. 2
is spontaneous and the β-hydroxy carbonyl compound cannot be isolated.
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920 Chapter 24 Carbonyl Condensation Reactions
The mechanism of dehydration consists of two steps: deprotonation followed by loss of –OH,
as shown in Mechanism 24.2.
Mechanism 24.2 Dehydration of a-Hydroxy Carbonyl Compounds with Base
(cid:150)OH new π bond
OH H O [1] OH (cid:150) O [2] O • In Step [1], base removes a proton from the α
CH C C C CH C C C CH CH CH C
3 3 3 carbon, thus forming a resonance-stabilized
H H H H H H + (cid:150)OH H enolate.
+ H O • In Step [2], the electron pair of the enolate
2
forms the π bond as –OH is eliminated.
OH O(cid:150)
CH C C C
3
H H H
resonance-stabilized enolate
This elimination mechanism, called the E1cB mechanism, differs from the two more general
Like E1 elimination, E1cB
mechanisms of elimination, E1 and E2, which were discussed in Chapter 8. The E1cB mecha-
requires two steps. Unlike
nism involves two steps, and proceeds by way of an anionic intermediate.
E1, though, the intermediate
in E1cB is a carbanion, not a Regular alcohols dehydrate only in the presence of acid but not base, because hydroxide is a poor
carbocation. E1cB stands for leaving group. When the hydroxy group is β to a carbonyl group, however, loss of H and OH
Elimination, unimolecular, from the α and β carbons forms a conjugated double bond, and the stability of the conjugated
conjugate base.
system makes up for having such a poor leaving group.
Dehydration of the initial β-hydroxy carbonyl compound drives the equilibrium of an aldol reac-
tion to the right, thus favoring product formation. Once the conjugated α,β-unsaturated carbonyl
compound forms, it is not re-converted to the β-hydroxy carbonyl compound.
Problem 24.3 What unsaturated carbonyl compound is formed by dehydration of each β-hydroxy carbonyl
compound?
HO CHO
O OH
a. O b. c.
HO
Problem 24.4 Acid-catalyzed dehydration of β-hydroxy carbonyl compounds occurs by the mechanism
discussed in Section 9.8. With this in mind, draw a stepwise mechanism for the following reaction.
HO H O O
H SO
CH C C C 2 4 CH CH CH C + H O
3 3 2
H H H H
24.1C Retrosynthetic Analysis
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.
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24.2 Crossed Aldol Reactions 921
HOW TO Synthesize a Compound Using the Aldol Reaction
Example What starting material is needed to prepare each compound by an aldol reaction?
O
OH H O
a. CH C C C b.
2
H H
Step [1] Locate the α and β carbons of the carbonyl group.
• When a carbonyl group has two different α carbons, choose the side that contains the OH group (in a
β-hydroxy carbonyl compound) or is part of the C––C (in an α,β-unsaturated carbonyl compound).
Step [2] Break the molecule into two components between the α and β carbons.
• The α carbon and all remaining atoms bonded to it belong to one carbonyl component. The β carbon and all remaining
atoms bonded to it belong to the other carbonyl component. Both components are identical in all aldols we have thus
far examined.
a. Break the molecule into two halves. b. Break the molecule into two halves.
OH H O O
β α
CH C C C
2
β α
H H
O
O H O O +
CH C + H C C
2
H H two molecules of cyclohexanone
two molecules of the same aldehyde

Problem 24.5 What aldehyde or ketone is needed to prepare each compound by an aldol reaction?
O
OH
a. CHO b. C6H5 C6H5 c.
OH
CHO
24.2 Crossed Aldol Reactions
In all of the aldol reactions discussed so far, the electrophilic carbonyl and the nucleophilic eno-
late have originated from the same aldehyde or ketone. Sometimes, though, it is possible to carry
out an aldol reaction between two different carbonyl compounds.
• An aldol reaction between two different carbonyl compounds is called a crossed aldol
or mixed aldol reaction.
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922 Chapter 24 Carbonyl Condensation Reactions
24.2A A Crossed Aldol Reaction with Two Different Aldehydes,
Both Having ` H Atoms
When two different aldehydes, both having α H atoms, are combined in an aldol reaction, four
different β-hydroxy carbonyl compounds are formed. Four products form, not one, because both
aldehydes can lose an acidic α hydrogen atom and form an enolate in the presence of base. Both
enolates can then react with both carbonyl compounds, as shown for acetaldehyde and propanal
in the following reaction scheme.
Four different products
OH
CH CHO
3
CH C CH CHO
3 2
α O (cid:150)OH, H O O H
2 (cid:150)
CH C CH C
3 2
OH
H H CH CH CHO
3 2
CH CH C CH CHO
acetaldehyde 3 2 2
H
two different enolates
OH
CH CHO
3
CH C CHCHO
3
α O (cid:150)OH, H2O (cid:150) O H CH3
CH CH C CH C
3 2
OH
H CH H CH CH CHO
3 3 2
CH CH C CHCHO
propanal 3 2
H CH
3
• Conclusion: When two different aldehydes have ` hydrogens, a crossed aldol reaction
is not synthetically useful.
24.2B Synthetically Useful Crossed Aldol Reactions
Crossed aldols are synthetically useful in two different situations.
• A crossed aldol occurs when only one carbonyl component has ` H atoms.
When one carbonyl compound has no ` hydrogens, a crossed aldol reaction often leads to
one product. Two common carbonyl compounds with no α hydrogens used for this purpose are
formaldehyde (CH ––O) and benzaldehyde (C H CHO).
2 6 5
For example, reaction of C H CHO (as the electrophile) with either acetaldehyde (CH CHO) or
6 5 3
acetone [(CH ) C––O] in the presence of base forms a single α,β-unsaturated carbonyl com-
3 2
pound after dehydration.
O ` H’s
[1] C H + CH CO (cid:150)OH, H2O OCH CH CHO CH CHCHO
3 2 (cid:150)H O
H H 2
cinnamaldehyde
Only this component from the enolate (component of cinnamon)
can form an enolate.
O
[2] C H + CH CO (cid:150)OH, H2O OCHCH CO CH CH CO
3 2 (cid:150)H O
CH3 H CH3 2 CH3
` H’s
The yield of a single crossed aldol product is increased further if the electrophilic carbonyl com-
ponent is relatively unhindered (as is the case with most aldehydes), and if it is used in excess.
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24.2 Crossed Aldol Reactions 923
Problem 24.6 2-Pentylcinnamaldehyde, commonly called fl osal, is a perfume ingredient with a jasmine-like odor.
Flosal is an α,β-unsaturated aldehyde made by a crossed aldol reaction between benzaldehyde
(CHCHO) and heptanal (CHCHCHCHCHCHCHO), followed by dehydration. Draw a stepwise
6 5 3 2 2 2 2 2
mechanism for the following reaction that prepares fl osal.
CHO
(cid:150)OH
C H CHO + + H O
6 5 CHO H O 2
2
flosal
(perfume component)
Problem 24.7 Draw the products formed in each crossed aldol reaction.
a. CH CH CH CHO and CH O c. C H CHO and O
3 2 2 2 6 5
b. C H COCH and CH O
6 5 3 2
• A crossed aldol occurs when one carbonyl component has especially acidic ` H atoms.
A useful crossed aldol reaction takes place between an aldehyde or ketone and a β-dicarbonyl
(or similar) compound.
R R Y
General NaOEt
reaction C O + Y CH2 Z EtOH C C
R’ R’ Z
R’ = H or alkyl Y, Z = COOEt, CHO,
new C(cid:150)C σ and π bonds
COR, CN
a-dicarbonyl compound
(and related compounds)
CHO COOEt
Example + CH (COOEt) NaOEt
2 2 EtOH COOEt
benzaldehyde diethyl malonate
As we learned in Section 23.3, the α hydrogens between two carbonyl groups are especially
acidic, and so they are more readily removed than other α H atoms. As a result, the a-dicarbonyl
compound always becomes the enolate component of the aldol reaction. Figure 24.2 shows
the steps for the crossed aldol reaction between diethyl malonate and benzaldehyde. In this type
of crossed aldol reaction, the initial β-hydroxy carbonyl compound always loses water to form
the highly conjugated product.
β-Dicarbonyl compounds are sometimes called active methylene compounds because they are
more reactive towards base than other carbonyl compounds. 1,3-Dinitriles and `-cyano carbonyl
compounds are also active methylene compounds.
Figure 24.2
The β-dicarbonyl compound
CH (COOEt)
Crossed aldol reaction 2 2 forms the enolate.
between benzaldehyde and NaOEt
CH (COOEt) O EtOH H O(cid:150)
2 2
(cid:150)
H CH(COOEt) CH(COOEt)
2 2
EtOH
The aldehyde is
the electrophile.
H OH
COOEt
CH(COOEt) (cid:150)H O
2 2
COOEt
not isolated
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924 Chapter 24 Carbonyl Condensation Reactions
O O O O O
Active methylene
compounds C C C C C N C CH C N
2
EtO CH OEt CH CH OEt CH CH CN
2 3 2 3 2
β-diester β-keto ester α-cyano 1,3-dinitrile
carbonyl compound
Problem 24.8 Draw the products formed in the crossed aldol reaction of phenylacetaldehyde (C H CH CHO) with
6 5 2
each compound: (a) CH (COOEt) ; (b) CH (COCH ) ; (c) CH COCH CN.
2 2 2 32 3 2
24.2C Useful Transformations of Aldol Products
The aldol reaction is synthetically useful because it forms new carbon–carbon bonds, generating
products with two functional groups. Moreover, the β-hydroxy carbonyl compounds formed in
aldol reactions are readily transformed into a variety of other compounds. Figure 24.3 illustrates
how the crossed aldol product obtained from cyclohexanone and formaldehyde (CH ––O) can be
2
converted to other compounds by reactions learned in earlier chapters.
Problem 24.9 What aldol product is formed when two molecules of butanal react together in the presence of
base? What reagents are needed to convert this product to each of the following compounds?
CHO
a. OH b. c. CH CH CH CH––C(CH CH )CH OH
3 2 2 2 3 2
d. CH CH CH CH––C(CH CH )CH(CH )OH
OH 3 2 2 2 3 3
Figure 24.3
aldol product
Conversion of a β-hydroxy
carbonyl compound into other O O OH
compounds
CH O OH NaBH OH
2 4
(cid:150)OH, H O CH OH
2 3
[1]
cyclohexanone β-hydroxy carbonyl 1,3-diol
compound
[2] (cid:150)OH, H O
2
OH O R OH O
NaBH4 [1] R M R
or
CH OH [2] H O
3 2
[3] [5]
allylic alcohol α,β-unsaturated (with RMgX) (with R CuLi)
2
carbonyl compound
[4] H , Pd-C
2
(1 equiv)
O
ketone
• The β-hydroxy carbonyl compound formed from the crossed aldol reaction can be reduced
with NaBH , CH OH (Section 20.4A) to form a 1,3-diol (Reaction [1]) or dehydrated to form an
4 3
α,β-unsaturated carbonyl compound (Reaction [2]).
• Reduction of the α,β-unsaturated carbonyl compound forms an allylic alcohol with NaBH (Reaction
4
[3]), or a ketone with H and Pd-C (Reaction [4]); see Section 20.4C.
2
• Reaction of the α,β-unsaturated carbonyl compound with an organometallic reagent forms two
different products depending on the choice of RM (Reaction [5]); see Section 20.15.
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24.3 Directed Aldol Reactions 925
24.3 Directed Aldol Reactions
A directed aldol reaction is a variation of the crossed aldol reaction that clearly defi nes which
carbonyl compound becomes the nucleophilic enolate and which reacts at the electrophilic car-
bonyl carbon. The strategy of a directed aldol reaction is as follows:
[1] Prepare the enolate of one carbonyl component with LDA.
[2] Add the second carbonyl compound (the electrophile) to this enolate.
Because the steps are done sequentially and a strong nonnucleophilic base is used to form the enolate
of one carbonyl component only, a variety of carbonyl substrates can be used in the reaction. Both car-
bonyl components can have α hydrogens because only one enolate is prepared with LDA. Also, when
an unsymmetrical ketone is used, LDA selectively forms the less substituted, kinetic enolate.
Sample Problem 24.1 illustrates the steps of a directed aldol reaction between a ketone and an
aldehyde, both of which have α hydrogens.
Sample Problem 24.1 Draw the product of the following directed aldol reaction.
O
CH
3 [1] LDA, THF
[2] CH CHO
3
[3] H O
2
2-methylcyclohexanone
Solution
2-Methylcyclohexanone forms an enolate on the less substituted carbon, which then reacts with
the electrophile, CH CHO.
3
H
O O O O(cid:150)H O HO H
C O
CH3 LDA CH3 (cid:150) CH3 CH3 C CH3 CH3 C CH3
THF H O
2
less substituted
new C(cid:150)C bond
kinetic enolate
Figure 24.4 illustrates how a directed aldol reaction was used in the synthesis of periplanone B,
the sex pheromone of the female American cockroach.
Figure 24.4 O
[1]
A directed aldol reaction in the O O O
LDA H
synthesis of periplanone B
THF (cid:150) [2] H2O
H OH
RO RO RO
deprotonation nucleophilic addition several
steps
O
O
O
periplanone B
sex pheromone of the female
American cockroach
• Periplanone B is an extremely active compound produced in small amounts by the female
American cockroach. Its structure was determined using 200 µg of periplanone B from more than
75,000 female cockroaches. This structure was confi rmed by synthesis in the laboratory in 1979.
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