Download 18.10 CONJUGATE ADDITIONS

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18.10
An attempt to form a Grignard reagent from 5-bromo2-pentanone is doomed to failure because the Grignard
will react with the carbonyl group.
■
2 Because the acetal group does not react with Grignard reagents
(or other basic or nucleophilic reagents), the Grignard reagent
can be prepared from this compound. The acetal is being used as
a protecting group for the carbonyl group.
1 Therefore, the carbonyl group is first protected as an
ethylene glycol acetal.
O
O
X
BrCH2CH2CH2CCH3
HO
OH
TsOH
5-Bromo-2-pentanone
O
C±
BrCH2CH2CH2±
CH3
1
2
OH
O
W
X
CH3CCH2CH2CH2CCH3
W
CH3
H3O
+
4
779
CONJUGATE ADDITIONS
–
O
O
O
W
C±
CH3CCH2CH2CH2±
CH3
W
CH3
O
X
CH3CCH3
3
Mg ether
O
O
C±
BrMgCH2CH2CH2±
CH3
6-Hydroxy-6-methyl-2-heptanone
4 When the reaction is worked up with aqueous acid, not only is the alkoxide group
protonated but the acetal is also hydrolyzed back to the ketone and ethylene glycol.
Easy removal is an important feature of protecting groups.
Figure 18.6
USE
OF AN ACETAL AS A PROTECTING GROUP.
PROBLEM 18.24
Because aldehydes are more reactive than ketones, it is possible to selectively form an
acetal group at the aldehyde group without also forming one at the ketone group of a
compound that contains both functional groups. Using this information, suggest how
the following transformation could be accomplished:
H±
O
Cœ
Cœ
H3C ± O
18.10
H±
O
Cœ
H3C±C±H
W
OH
Conjugate Additions
When a CC double bond is conjugated with a carbonyl group, the double bond often
has chemical reactions that are similar to those of the carbonyl group. (Recall from
Section 12.3 that the carbon adjacent to the carbonyl group is sometimes called the
3 This Grignard reagent reacts
like any other Grignard reagent.
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CHAPTER 18
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ADDITIONS TO THE CARBONYL GROUP
-carbon. The next carbon is called the -carbon, and so on. Therefore, a compound
with a double bond conjugated to the carbonyl group is said to be , -unsaturated.)
The -carbon of an , -unsaturated carbonyl compound is electrophilic, very similar
to the carbonyl carbon. This can best be understood by examination of the resonance
structures for such a conjugated compound:
1
–
–
.. O ..
±
C±
±
3 C 2 CH3
X
C±
H ±4 H
H±
W
C±
C ±+ CH3
W
C±
C±
CH3
W
C±
H ±+ H
H±
±
H±
..
.. O ..
..
.. O
..
-Carbon
C±
H±
H
-Carbon
Electrophilic
carbons
When a nucleophile reacts with an , -unsaturated carbonyl compound, it may bond to
either of the two electrophilic carbons. If it bonds to the carbonyl carbon, the reaction
is termed a normal addition or a 1,2-addition (because the nucleophile and electrophile
have added to adjacent positions). If, instead, it bonds to the -carbon, the reaction is
termed a conjugate addition or a 1,4-addition. The following mechanism operates under basic conditions:
.. O ..–
±
±
W
C±CH3
C±
Nu
X
C±
H±
H
H±
H±A
W
C±CH3
C±
Nu
X
C±
H±
H
H±
±
C±
H±
H
normal
addition
.. Nu–
..
C±
C ± CH3
±
H±
.. O±H
..
..
.. O
conjugate . –
addition . Nu
±
W
C±
H±
CH3
C±
W
H±C±H
W
Nu
.. O
H±A
W
C±
H±
CH3
C±
W
H±C±H
W
Nu
..
..
C±
C ± CH3
W
H±C±H
W
Nu
.. O±H
..
–
H±
–
.. O ..
..
..
.. O
tautomerize
H X
W C±
CH3
H±C ±
W
H±C±H
W
Nu
The normal addition process is identical to the other reactions that have been encountered so far in this chapter: The nucleophile bonds to the carbonyl carbon and the electrophile bonds to the oxygen of the carbonyl group. In a conjugate addition the
nucleophile bonds to the -carbon. The electrophile, a proton, can bond to either the carbon or the oxygen of the resonance stabilized anion. It actually reacts faster at the
oxygen, producing an enol in an overall 1,4-addition. However, as discussed in Section
11.6, enols are less stable than the carbonyl tautomers, so the product that is isolated
contains the carbonyl group.
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18.10
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CONJUGATE ADDITIONS
The overall result of a conjugate addition is the addition of a proton and a nucleophile to the CC double bond. However, this reaction differs greatly from the additions discussed in Chapter 11, in which the electrophile adds first. Here, the nucleophile
adds in the first step. This reaction does not occur unless there is a group attached to the
double bond that can help stabilize, by resonance, the carbanion intermediate. In many
cases this is the carbonyl group of an aldehyde or a ketone. However, other groups, such
as the carbonyl group of an ester or a cyano group, also enable this reaction to occur.
Whether a normal or a conjugate addition occurs depends on both the structure of
the ,-unsaturated electrophile and the nature of the nucleophile. The less reactive nucleophiles usually give conjugate addition because the reactions are reversible and the
conjugate addition product is more stable. Thus, cyanide ion and amines add in a conjugate manner as shown in the following examples:
HCN
CH3CH2OH
H2O
O
O
X
X
C±
C±
CH3CH2O ±
C±
OCH2CH3
X
C±
Ph ±
H
NaCN
CH3CH2OH
H2O
CPN
H
W
C±
X
PhNH
C±
H±
H
(96%)
O
O
X H X
C± W C±
CH3CH2O ±
C±
OCH2CH3
W
Ph±C±H
W
CN
O
X
C±
H±C ± CH3
W
H3C±C±CH3
W
NH2
H
NH3
H2O
±
O
X
H±
C±
C ± CH3
X
C±
H3C ±
CH3
H±
O
X
C±
H±C ±
Ph
W
Ph±C±H
W
CN
H
±
O
X
H±
C±
Ph
C±
X
C±
Ph ±
H
H
W CPN
H±C ±
W
PhN±CH2
W
H
(70%)
(78%)
For the more reactive nucleophiles, where addition is essentially irreversible, whether
1,2-addition or 1,4-addition occurs depends on the relative rates of addition to the two
electrophilic sites, the carbonyl carbon and the -carbon. Lithium aluminum hydride usually gives predominantly 1,2-addition and provides a useful way to reduce the carbonyl
group of an ,-unsaturated compound. Sodium borohydride, on the other hand, often
gives a mixture of 1,2-addition and the completely reduced product, where 1,4-addition
followed by 1,2-addition has occurred. Thus, the reaction of 2-cyclohexenone with lithium
(95%)
781
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CHAPTER 18
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ADDITIONS TO THE CARBONYL GROUP
aluminum hydride gives a good yield of the 1,2-addition product, 2-cyclohexenol. In contrast, reaction with sodium borohydride is less useful because of the mixture of products
that is formed. Part of the reaction occurs by 1,2-addition to produce 2-cyclohexenol and
part by 1,4-addition to produce cyclohexanone, which is then reduced further to cyclohexanol.
O
OH
H
H
H
OH
H
1) LiAlH4
2) H O+
H
H
3
H
H
H
H
2%
91%
2-Cyclohexenone
2-Cyclohexenol
(1,2-addition)
NaBH4
CH3OH
Cyclohexanol
(1,4- followed
by 1,2-addition)
53%
37%
1) CH3CH2CH2MgBr
ether
2) H O+
3
HO
H±
±
O
X
H±
C±
H
C±
X
C±
H3C ±
H
±
In the case of a Grignard reagent reacting as the nucleophile, the amounts of normal addition and conjugate addition depend on the steric hindrance at the carbonyl carbon and the -carbon. Reaction with an ,-unsaturated aldehyde usually results in the
formation of the product from attack at the unhindered aldehyde carbon (1,2-addition),
as shown in the following equation:
H
C±
C ± CH2CH2CH3
X
C±
H3C ±
H
(78%)
Because of the increased steric hindrance at the carbonyl carbon, similar reactions involving ,-unsaturated ketones often result in a mixture of 1,2- and 1,4-addition. The
exact amount of each product depends on the relative amounts of steric hindrance at the
two electrophilic carbons and may be difficult to predict in advance. An example is provided in the following equation:
An ,-unsaturated
ketone
1) CH3CH2MgBr
ether
2) H O+
3
O
H X
W C±
H±
C±
H±C ± CH3
C ± CH2CH3 W
X
H3C±C±CH2CH3
C±
W
H3C ±
H
H
HO
±
O
X
H±
C±
C ± CH3
X
C±
H3C ±
H
±
782
CH3
41%
39%
1,2-Addition
1,4-Addition
If conjugate addition of an organometallic nucleophile is desired, this can be accomplished by using a lithium diorganocuprate reagent, which has the organic group at-
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18.10
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CONJUGATE ADDITIONS
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tached to a copper atom. These reagents are prepared by the reaction of organolithium
compounds with copper(I) salts such as cuprous iodide, as illustrated in the following
equation for the preparation of lithium dimethylcuprate:
2 CH3Li CuI
(CH3)2CuLi LiI
Methyllithium
Lithium dimethylcuprate
The reactions of lithium diorganocuprates with ,-unsaturated carbonyl compounds give excellent yields of 1,4-addition products:
O
O
(CH2œCHCH2)2CuLi
78°C
THF
+
H3O
(94%)
CH2CHœCH2
O
X
H±
C±
C ± OCH2CH3 (CH3)2CuLi
X
C±
CH3(CH2)5±
H
+
H3O
toluene
O
H X
W C±
H±C ± OCH2CH3
W
CH3(CH2)5±C±CH3
W
H
(86%)
In summary, lithium aluminum hydride usually gives good yields of 1,2-addition
products, that is, unsaturated alcohols. The reaction of Grignard reagents with ,-unsaturated aldehydes also gives good yields of 1,2-addition products. Nucleophiles that give
good yields of 1,4-addition products are cyanide ion, amines, and lithium diorganocuprate
reagents. The cuprate reagents provide an excellent method to add a carbon nucleophile
to the -carbon of ,-unsaturated carbonyl compounds, a process that is very useful in
synthesis.
PROBLEM 18.25
Show the products of these reactions:
O
O
H
a)
1) CH3MgI
2) NH4Cl, H2O
O
X
c) CH2œCHCCH3
1) LiAlH4
2) H O+
3
e)
O
Click Coached Tutorial Problems
to practice Conjugate
Addition Reactions.
1) (CH3)2CuLi
2) H O+
3
b)
1) (CH3CH2)2CuLi
2) H O+
3
O
X
d) CH2œCHCOCH3
HCN
CH3OH