CHAPTER 18
DIFUNCTIONAL CARBONYL COMPOUNDS
18.1 INTRODUCTION
It is a recurring motif of organic reactivity that two functional groups close to each other
affect each other's reactivity, and that oftentimes the difunctional compound reacts in ways that
neither monofunctional compound to which it is related does. This was true of the dienes, for
example, which react by either the 1,2- or 1,4-addition mode; the 1,4-addition reaction has the
absolute requirement of a conjugated diene system; reductive elimination of vicinally substituted
halides (haloethers, haloesters or dihalides) is another example of a reaction that occurs only
when two functional groups are in a proximal relationship. In this chapter, we will study the
reactions of difunctional compounds where one of the interacting functional groups is a carbonyl
group.
The placement of a double bond in a molecule such that it is conjugated with a carbonyl
group has a dramatic effect on the reactivity of the double bond: The LUMO energy of most
simple alkenes is too high for alkenes to react with nucleophiles, so nucleophilic addition to a
simple alkene is an extremely rare reaction. When the double bond is conjugated with a carbonyl
group, however, it becomes very susceptible to addition of nucleophiles, and the 1,4-addition
reaction of nucleophiles to conjugated carbonyl compounds is an important synthetic method in
organic chemistry. In a similar fashion, when two carbonyl groups are located within a molecule
so they are β to each other, the dicarbonyl compound becomes unusually acidic, so that the
hydrogens of the methylene group between the carbonyl group may be replaced by alkyl groups
under quite mild conditions. If one of the carbonyl groups is a carboxyl group, the carboxylic
acid is also extremely susceptible to decarboxylation under quite mild conditions.
18.2 REACTIONS OF α-HALOKETONES
A halogen atom α to a carbonyl group is particularly reactive in SN2 reactions (which makes
α-halocarbonyl compounds popular as ingredients of tear gases), and it is readily displaced by a
variety of nucleophiles including sulfur and phosphorus nucleophiles. However, the presence of
the halogen atom also renders the α hydrogens more acidic than in an unsubstituted ketone.
This presents a problem when the nucleophile to be used is also a reasonably strong base (e.g.
hydroxide ion or alkoxide ions, RO–). The two most common reactions involving α-haloketones
and bases are the haloform reaction and the Favorskii rearrangement.
Haloform reaction
Base-catalyzed halogenation of a methyl ketone is typically under kinetic control, so that it
gives the α,α,α-trihaloketone where all three methyl hydrogens have been replaced by the
halogen. The trihalomethyl group is an electron-withdrawing group rather than an electronreleasing group; it renders the carbonyl group much more susceptible to nucleophilic addition,
and it can even serve as a leaving group. When such trihalo compounds are formed in the
presence of a nucleophilic base (e.g. hydroxide anion), the nucleophilic addition is followed by
loss of the trihalomethide anion, CX3–, to give the carboxylic acid. The trihalomethide anion
then removes a proton from the carboxylic acid or the solvent to give the corresponding
DIFUNCTIONAL CARBONYL COMPOUNDS
Chapter 18 676
trihalomethane, or haloform – hence the name of the reaction.
mechanism of the haloform reaction is given in Figure 18.1.
O
Br2/KOH/H2O
CH3
The currently accepted
••
O
O
CBr3
CBr3
OH
••
HO
CHBr3
O
O
O
OH
+
+
CBr3
Figure 18.1 The currently-accepted mechanism of haloform reaction.
The Haloform Reaction. This reaction, which was discovered in 1822 as a method for forming
iodoform, and whose use was expanded in 1832 as a method for forming chloroform, had fallen into
relative obscurity by the 1980's. However, the reaction has again risen to a position of prominence
following the finding in the 1980's that chloroform may cause cancer in laboratory animals, and its addition
to the list of suspected carcinogens. This finding, which received considerable press exposure in the 1980's
because of the rise of chloroform levels in drinking water, has sparked a new debate on what organic
compounds are safe to dispose of into the water system because the chloroform produced is not removed
by normal water treatment protocols. In a chlorinated water system, compounds such as ethanol and
acetone are converted to chloroform, and it is now recommended that these compounds no longer be
disposed of in the water system.
The Favorskii rearrangement
Prior to the development of methods based on sulfur and selenium compounds for
introducing a double bond into a position α to a carbonyl group, the normal sequence involved
halogenation and elimination of the hydrogen halide. However, this reaction is not without its
problems, as was discovered by Russian chemist Alexei Yevgrafovich Favorskii. Favorskii
observed that the base-promoted elimination of halogen from α-haloketones was accompanied by
the formation of carboxylic aid derivatives with a rearranged carbon skeleton. Where the ketone
is not symmetrical, two products are usually obtained in unequal amounts. Some typical
examples follow.
O
CH3O
CO2CH3
Cl
O
CH3O
Cl
O
OCH3
+
OCH3
O
This reaction, which is now called the Favorskii (or Favorski, or Favorsky) rearrangement,
has been the subject of intensive investigation, including isotopic labeling studies. There is now
an impressive body of experimental evidence to support the view that it proceeds through a
cyclopropanone intermediate, as shown in Figure 18.2. The steps in this rearrangement reaction
are all simple reactions of ketones. In the first step, the nucleophile reacts as a base to remove an
acidic α hydrogen. The enolate anion generated now undergoes an intramolecular SN2
displacement of the halogen to give the cyclopropanone intermediate. The cyclopropanone is
particularly susceptible to addition of nucleophiles, and so it undergoes addition of the nucleophile
to give the hemiketal anion which then undergoes ring opening to relieve the strain in the threemembered ring.
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
O
R1
R1
•O•
X
H
R2
R2
OR
X
R1
•O• OR
O
R1
R2
R1
R1
R2
R2
R2
R1
R1
R2
R2
RO
O
O
R2
H
R2
RO
R1
R1
RO
R1
R1
R2
R2
Figure 18.2 The currently accepted mechanism of the Favorskii rearrangement involves a cyclopropane
intermediate.
Alexei Yevgrafovich Favorskii (1860-1945). Favorskii was born in Pavlovo, in the Gorky region of
Russia, and educated at the University of St. Petersburg, where he was one of the outstanding students of
Butlerov. After his graduation in 1882, he remained at St. Petersburg as a member of the faculty there,
becoming professor in 1896. Favorskii's research was primarily involved with the acetylenes and the
rearrangements of carbanionic species. He developed the first useful industrial synthesis of isoprene and
methods that are still used today for the formation of acetylenic alcohols. His discovery of the
isomerization of alkynes in the presence of bases was first reported in 1884, while his discovery of the
base-promoted isomerization of α-substituted carbonyl compounds was first reported in 1891. In 1891, he
also predicted the existence of compounds possessing cumulative double bonds. Favorskii assembled a
large research group at St. Petersburg, including such luminaries as Nazarov, and Ipatieff. A most amiable
picture of Favorskii is painted by his student, Vladimir Ipatieff, in his memoirs – it is Favorskii who gave
him the advice given in the beginning of this book. In 1929, Favorskii was appointed a full member of the
Soviet Academy of Science. From 1900 to 1930, he was editor of the premier Russian chemical journal.
Reaction synopsis
Haloform Reaction
O
CH3
R
Reagents:
or
X2
base
O
O
or
O
R
OR
R
Cl2/KOH/H2O, Br2/KOH/H2O, I2/KOH/H2O [give carboxylate anion]
Cl2/NaOR/ROH, Br2/NaOR/ROH, I2/NaOR/ROH [give ester]
Favorskii Rearrangement
R′
O
R
R X
R′′O
R′′O
O
R
R R′
X = halogen or other good leaving group
KOH, KOR′′, etc.
Reagents:
Sample Problem 18.1. What will be the major organic product obtained from each of the
reactions below?
Br
KOMe/MeOH
(a)
O
(b)
O
NaOCl/H2O
677
DIFUNCTIONAL CARBONYL COMPOUNDS
(c)
Chapter 18 678
Br
Br2/KOH/H2O
NaOEt
(d)
O
O
Answers:
O
(a)
OH
(b)
CO2Me
(c)
O
HO
CO2Et
(d)
Problem 18.1. What will be the major organic product obtained from each of the
reactions below?
Br
(a)
O
KOMe/MeOH
(b)
O
NaOCl/H2O
18.3 α,β-UNSATURATED CARBONYL COMPOUNDS
Conjugate addition
The only site where nucleophiles can add to saturated aldehydes and ketones is the the
carbonyl carbon. However, when the carbonyl group is conjugated with another double bond
the situation is not quite so straightforward, as the examples below show. When a nucleophile
adds to an α,β-unsaturated carbonyl compound, it may add at the carbonyl carbon (1,2-addition)
or at the β carbon (1,4-addition). The 1,4-addition reaction is seldom referred to by that term.
Instead, it is usually termed conjugate addition, or Michael addition, after American chemist
Arthur Michael, who first described the 1,4-addition of certain enolate anions to conjugated
carbonyl compounds (strictly speaking, the term "Michael addition" should be restricted to
additions of enolate anions, but it is widely used to describe all 1,4-additions).
C6H5SH/KOH
C6H5S
O
O
Li
RO
CHO
OH
RO
(90%)
Et2O/0°C
O
O
CH2=CH–C≡N/NaOMe
N≡C
(67%)
Et2O/r.t./2 h.
CN
CN
KCN/H2O/CH3OH
Et2O/Δ
(92-94%)
CN
(both stereoisomers)
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
Which product will predominate depends on three factors:
1) The structure of carbonyl compound – conjugated aldehydes usually undergo 1,2addition, while conjugated ketones and nitriles tend to undergo 1,4-addition.
2) The identity of the nucleophile – nucleophiles which add irreversibly to saturated
carbonyl compounds give mainly 1,2-addition, while nucleophiles which add reversibly tend to
give 1,4-addition.
3) The presence or absence of a strong acid catalyst – under basic conditions, nucleophiles
which add reversibly to saturated carbonyl compounds give the product of conjugate addition
with α,β-unsaturated carbonyl compounds; under strong acid catalysis the 1,2-adduct usually
predominates.
Arthur Michael (1853-1942). Michael was born in Buffalo, New York. In 1871 he travelled to
Berlin to study chemistry under Hofmann, and in 1872 he travelled to Heidelberg, where he studied for two
years under Bunsen before returning to Berlin, where he spent the next three years under Hofmann's
tutelage. He spent 1879 working with Wurtz in Paris and Mendeleev in Russia, and he then returned to the
United States. He was Professor of Chemistry at Tufts College from 1880-1891 and from 1894-1907, and
Professor of Chemistry at Harvard University from 1912 until 1936. In 1879 Michael accomplished the
first synthesis of a natural glucoside (helicin), he was among the first to develop synthetic methods based
on malonic esters, and in 1887 he discovered the conjugate addition of enolate anions to conjugated
carbonyl compounds and nitriles that now bears his name. His work in physical organic chemistry
pioneered the applications of thermodynamics in organic chemistry, and he made major contributions to the
theory of organic reactivity. Michael's keen insights made him an ideal critic of then-accepted theories, and
on more than one occasion he devised experiments that forced a re-evaluation of theory.
The kinetically favored attack upon an α,β-unsaturated carbonyl compound is at the carbonyl
carbon. However, when a nucleophile adds to the carbonyl carbon of a conjugated π system, the
product is a simple alkene, so that all the resonance stabilization of the conjugated system is lost.
In contrast to this, the initial product of conjugate addition of a nucleophile to a conjugated
carbonyl compound is an enolate anion – a resonance-stabilized intermediate. This is the
thermodynamically favored addition pathway (Figure 18.3).
nucleophilic attack
favored here
thermodynamically
O
O
Nu
1,2
O
1,4
Nu
Intermediate not
resonance-stabilized
nucleophilic attack
favored here kinetically
Nu
••
O
Intermediate
resonance-stabilized
Figure 18.3 The addition of a nucleophile to an α,β-unsaturated carbonyl system may occur to give the 1,2adduct (the kinetically favored product) or the 1,4-adduct (the thermodynamically favored product).
Why do nucleophiles add to the alkene π bond of conjugated carbonyl compounds and
conjugated nitriles when they do not add to simple alkenes? In a non-conjugated alkene,
aldehyde or ketone, the LUMO is a π* orbital. The π* orbital of a carbonyl group is of relatively
low energy, so nucleophilic addition is an important reaction of aldehydes and ketones; the
LUMO of a simple alkene is not, so that alkenes do not normally react with nucleophiles.
However, when a carbonyl group is conjugated with an alkene the π orbitals encompass all four
atoms; the LUMO of this π orbital system is ψ3. The energy of this orbital is low enough that it
is energetically accessible to an attacking nucleophile. Since the LUMO also has lobes at the β
carbon as well as at the carbonyl carbon, an attacking nucleophile may now add at the carbonyl
carbon or at the β carbon. This is a major modification of the reactivity of the alkene double
679
DIFUNCTIONAL CARBONYL COMPOUNDS
Chapter 18 680
bond – the alkene double bond of an α,β-unsaturated carbonyl compound is susceptible
to nucleophilic addition.
One may also invoke resonance arguments to rationalize the experimental observations. In
the saturated carbonyl compound, there is only one dipolar canonical form, with the positive
charge carbon, so the addition of nucleophiles is restricted to addition to the carbonyl carbon. In
an α,β-unsaturated carbonyl compound, however there are two dipolar canonical forms with the
positive charge on carbon – one with the positive charge on the carbonyl carbon and one with
the positive charge on the β carbon atom. Thus, one would predict that conjugated carbonyl
compounds would react with nucleophiles at either the carbonyl carbon or the β carbon. The π
molecular orbitals of an α,β-unsaturated carbonyl compound and the three most important
canonical forms of an α,β-unsaturated carbonyl compound are illustrated in Figure 18.4.
O
ψ4
O
ψ3
O
O
O
LUMO
O
O
ψ2
O
O
ψ1
O
O
Figure 18.4 The π molecular orbitals (left) and the canonical forms contributing to the resonance hybrid of
an α,β-unsaturated carbonyl system (right).
Table 18.1 contains an overview of the reactivity of conjugated carbonyl compounds with
nucleophiles. Organolithium reagents add to α,β-unsaturated carbonyl compounds to give the
1,2-adduct. However, as the metal becomes less electropositive (i.e. as the organometallic reagent
becomes more covalent), the tendency to give the 1,4-adduct increases. Grignard reagents alone
give mainly 1,2-adduct with some 1,4-adduct; in the presence of copper salts, Grignard reagents
add to conjugated ketones to give the 1,4-adduct almost exclusively.
Alkylcopper reagents, R-Cu, are not nucleophilic enough to react most carbon electrophiles
(alkyl halides and carbonyl compounds). The nucleophilicity of these unreactive organocopper
reagents can be dramatically enhanced, however, by converting them to lithium
dialkylcuprates by combining them with alkyllithiums. Cuprates, which formally contain
copper-based cuprate anions R2Cu–, are good nucleophiles that readily add to conjugated
carbonyl compounds and nitriles to give 1,4-adducts.
O
H
O
O
O
CH3O
H
CH2=CH–Li/CuI
Bu3P/Et2O/
-78°C to 0°C/1.5 h
2 CH2=CH–Li + CuI
O
O
(95%)
CH3O
[(CH2=CH)2Cu]Li + LiI
Cuprate reagents are usually formed by the reaction between an alkyllithium and a copper
salt, as discussed in Chapter 8. Cuprates based on salts such as cuprous cyanide or cuprous
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
alkynides are called higher order cuprates because they formally contain anions of the type
R2CuX2–. Higher order cuprates tend to be stronger nucleophiles than lithium dialkylcuprates,
and they have become much more popular than the simple lithium dialkylcuprates in recent years
– especially when the alkyl group is complex or expensive.
Table 18.1 Predominant outcome of nucleophilic addition to conjugated compounds
Nucleophile
H2O or OH–
ROH/H+
RO–
ROO–
RNH2
RSH/H+
RS–
CN–
enolate anions
enamines
phosphorus ylides
sulfur ylides
RMgX
RLi
LiAlH4
R2CuLi
aldehyde
1,2
1,2*
1,2 and 1,4
1,2 and 1,4
1,2 and 1,4
1,2
1,4
1,2
1,2
1,4
1,2
1,2
1,2
1,2
1,2
1,2 and 1,4
ketone
1,4
1,2*
1,4
1,4
1,4
1,2 and 1,4
1,4
1,4
1,4
1,4
1,2
1,2 or 1,4**
1,2
1,2
1,2
1,4
nitrile or ester
1,4
1,4
1,4
1,4
1,4
1,4
1,4
1,4
1,4
1,4
–
1,2
1,2
1,2
1,4
*These reactions may be accompanied by migration of the double bond.
**If the ylide is based on dimethyl sulfide, the addition is 1,2; if it is based on dimethyl sulfoxide, the addition
is 1,4.
Phosphorus ylides always give the 1,2-addition product when they react with conjugated
carbonyl compounds. In contrast to this, the product formed by addition of the corresponding
sulfur ylides to conjugated carbonyl compounds depends on the nature of the sulfur ylide itself.
If the ylide is based on a simple dialkyl sulfide, the ylide adds in a 1,2- manner to give the
epoxide, as expected. If it is based on a dialkyl sulfoxide, however, the product formed is a
cyclopropyl ketone, formed by initial conjugate addition of the ylide. Sulfoxonium ylides are
considerably less reactive than sulfonium ylides due to the presence of the oxygen atom, which
helps to stabilize the negative charge on the carbanion. The regiochemistry of the reactions of
sulfur ylides has been interpreted in terms of irreversible addition of the simple sulfonium ylide to
the carbonyl group so that the product is derived from the 1,2-adduct, and reversible addition of
the less reactive sulfoxonium ylide so that the product is derived from the 1,4-adduct.
O
O
Me2S=CH2
O
Me2S(O)=CH2
A reaction which is mechanistically similar to the reaction between a sulfoxonium ylide and a
conjugated carbonyl compound is the reaction of a coinjugated carbonyl compound with an
alkaline peroxide. In this reaction, the peroxy anion adds in a 1,4 fashion to the double bond, and
the intermediate enolate anion displaces hydroxide ion (or an alkoxide ion)) to give the epoxide as
the final product.
681
DIFUNCTIONAL CARBONYL COMPOUNDS
Chapter 18 682
O
O
O
H2O2/NaOH
O
O
The data in Table 18.1 illustrate one very important facet of the reactions between heteroatom
nucleophiles and α,β-unsaturated carbonyl compounds. When an α,β-unsaturated ketone is
treated with an alkoxide anion in an alcohol solvent, the product obtained is the 1,4-adduct.
However, when the same ketone is treated with the same alcohol under conditions of acid
catalysis, the ketal is formed preferentially. These two competing reaction pathways are shown in
Figure 18.5.
O
O
ROH
RO
O
RO
RO O
RO
RO OH
ROH
RO
major
minor
BASE CATALYSIS
H
O
OH
OH
ROH
RO
RO OH
RO OH
ROH
RO
H
(slow) (slow)
RO OR
O
ROH
major
OR
OH
dienol
ACID CATALYSIS
H
RO OR
ROH
minor
Figure 18.5 The addition of alcohols to cyclohexanone depends on the conditions used: under acidic
conditions, 1,2-addition predominates; under basic conditions, 1,4-addition predominates.
The reaction shown in Figure 18.5 illustrates another important feature of the reactions of
conjugated aldehydes and ketones under strong acid catalysis: the migration of the double bond.
This very common reaction occurs because the addition reaction is reversible under acid catalysis,
so that the thermodynamically more stable dienol can participate as an intermediate in the
reaction. Ketals of saturated ketones tend to be more stable than ketals of conjugated ketones
(why?), and the major final product of the reaction is the ketal of the non-conjugated ketone.
Not unexpectedly, similar behavior is observed with sulfur nucleophiles: basic reaction conditions
favor conjugate addition and acidic conditions favor 1,2-addition.
Sample Problem 18.2. Draw the structure of the major organic product that should be
produced in the reaction between each of the reagents in the list below and:
(a) cyclopentenone
(1) CH3S–K+ /CH3OH.
(4) (C6H5)3P=CH2.
Answers:
(b) acrolein.
(2) CH3Li/Et2O.
(3) 1) LiAlH4/Et2O; 2) H3O+ .
(5) HOCH2CH2OH/TsOH/C6H6/Δ.
(6) KCN/CH3OH.
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
O
OH
OH
(a) (i)
(ii)
(iii)
O
CH2
(iv)
(v)
O
O
(vi)
CH3S
CN
CHO
(b) (i)
OH
(ii)
OH
(iii)
(iv)
(v)
O
CN
O
(vi)
HO
CH3S
Problem 18.2. Draw the structure of the major organic product which should be
produced in the reaction between the carbonyl compounds in the first list below and
the reagents in the second list. [Do only parts (i)-(v) for the nitrile and ester].
Compounds:
(a) 2-cyclohexenone.
(c) 2-methylcyclopentanone.
(e) 1-cyclohexenecarbonitrile.
Reagents:
(i) CH3CH2S–K+ /CH3OH.
(iii) 1) LiAlD4/Et2O; 2) H3O+ .
(v) KCN/CH3OH.
(vii) HOCH2C(CH3)2CH2OH/TsOH/C6H6/Δ.
(b) crotonaldehyde.
(d) 4-methyl-3-penten-2-one.
(f) methyl fumarate.
(ii) CD3Li/Et2O.
(iv) LiCu(CH3)2/THF.
(vi) (C6H5)3P=C(CH3)2.
α,β-Unsaturated carboxylic acid derivatives
The reactions of α,β-unsaturated carboxylic acid derivatives mimic those of the corresponding
conjugated ketones and aldehydes. Conjugated esters, amides and nitriles readily undergo
conjugate addition reactions with nucleophiles, including cuprate reagents, simple enolate anions,
and malonic ester anions, in just the same way as conjugated aldehydes and ketones, a reaction
which we discussed in Section 11.5.
CH3O
CH3O
1) LDA/THF/-78°C
2) EtO2C-CH=CH-CO2Et
3) H3O
O
CO2Et
EtO2C
CO2Et
O
1) Me2CuLi/THF
CO2Et
2) MeOH
CO2Et
N≡C
+
CO2Et
1) NaOEt/EtOH
2) H2O
N≡C
CO2Et
CO2Et
(57-63%)
Conjugated carboxylic acid derivatives also react as dienophiles in the Diels-Alder
cycloaddition reaction. In fact, conjugated carboxylic acid derivatives may be the most widelyused dienophiles in the Diels-Alder reaction. The presence of the carbonyl group renders the
double bond more electrophilic, so that the cycloaddition proceeds more readily.
683
DIFUNCTIONAL CARBONYL COMPOUNDS
Chapter 18 684
H
CO2Me
+
CO2Me
OMe
OMe
Me3SiO
Me3SiO
+
H
CO2Me
CO2Me
Oxidative decarboxylation of conjugated carboxylic acid derivatives by the Hofmann or
Curtius rearrangements occurs by the same mechanism as discussed earlier. In these reactions,
however, the intermediate amino compound is an enamine that rapidly tautomerizes to the imine
form. Acid hydrolysis of the imine under mild conditions gives the corresponding aldehyde or
ketone.
CON3
NH
O
H3O+
Δ
CON3
NH2
N=C=O
N=C=O
NH2
NH
enamine
O
imine
Alkylation and hydrogen exchange in conjugated carbonyl compounds
Unlike their saturated counterparts, the two α carbons of an α,β-unsaturated ketone are not
equivalent. Under conditions of kinetic control, the deprotonation of the compound occurs at the
sp3-hybridized α carbon to give a cross-conjugated enolate anion. Under conditions of
thermodynamic control, however, the deprotonation occurs at the γ carbon to give the
corresponding linearly-conjugated enolate. Of the two, the linear anion is more stable than the
cross-conjugated anion.
O
O
KOCMe3/Me3COH
(thermodynamic)
O
LDA/THF/-78°C
(kinetic)
The terms cross-conjugated and linearly-conjugated arise from the way in which the lone
pairs on the oxygen and the double bonds interact. In the cross-conjugated system, the lone pairs
can interact with only one of the double bonds, so that the system can be described in terms of
two independent conjugated systems – a 1,3-diene and an enolate anion – without introducing
serious errors in predicting its reactivity. In the linearly-conjugated system, on the other hand,
the lone pair on oxygen can be delocalized along the entire conjugated system – there is only one
conjugated system in this case, and all five atoms belong to it simultaneously.
The kinetic enolate of a conjugated carbonyl compound has only one nucleophilic carbon
atom, so it reacts like its saturated counterpart in alkylation reactions to give the products
expected. The thermodynamic enolate of a conjugated system, however, has two nucleophilic
carbon atoms: the α carbon and the γ carbon. Under kinetic conditions, alkylation occurs at the
α carbon to give the α-alkyl-β,γ-unsaturated carbonyl compound which then reacts with the base
to restore the conjugation in the system. This reactivity pattern can be seen by resonance, where
there are two canonical forms with the lone pair on carbon, or in the HOMO of the dienolate
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
anion, which has three lobes: one on the oxygen, and one at the α and γ carbons. The orbital
coefficients of the HOMO are such that the largest lobe (the preferred site of overlap with the
LUMO of an electrophile) in on the α carbon.
O
O
kinetic enolate: only one nucleophilic carbon
O
O
O
O
••
HOMO of enolate anion
thermodynamic enolate: two nucleophilic carbons
Thermodynamic alkylation of enones often gives rise to polyalkylated products, as shown
below.
MeO
O
MeO
O
O
KOCMe3/MeI/Me3COH
O
O
O
O
(81%)
O
Just as the treatment of a saturated carbonyl compound with a base and a deuterated protic
solvent gives a product in which the acidic α hydrogens have been exchanged for deuterium, so
the treatment of conjugated carbonyl compounds with the same reagent leads to the exchange of
the α hydrogens, and the γ hydrogens of the enone.
D
D
O
KOD/D2O
D
(repeat several times)
O
D
D D
Sample Problem 18.3. What should be the major product obtained when 3-methyl-2cyclohexenone is treated with each of the reagents in the following list?
(a) 1) LDA/THF/-78°C; 2) CH3I/-78°C.
(b) KOC(CH3)3/(CH3)3C-OD.
(c) 1) LDA/THF/-78°C; 2) D2O.
(d) KOC(CH3)3/(CH3)3COH/CH3I/Δ.
Answers:
D
O
(a)
CH3
CH3
(b)
O
CD3
D
D
D
CH3
O
(c)
D
CH3
(d)
O
CH3
CH3
D
Problem 18.3. Draw the structure of the major organic product expected from the
reaction between each of the following compounds with the list of reagents given in
Sample Problem 18.3.
(i) 2-methylcyclohexenone.
(iii) 4-methyl-3-penten-2-one.
(ii) 3-ethylcyclohexenone.
Problem 18.4. The following compound occurs naturally in the oil of the Australian
sandalwood tree, Eremophila mitchelli. How many deuterium atoms will be
685
DIFUNCTIONAL CARBONYL COMPOUNDS
Chapter 18 686
incorporated into this molecule on repeated treatment with KOC(CH3)3 in
(CH3)3COD? Draw the structure of the product, showing the location of the
deuterium atoms.
O
O
Reduction of Conjugated Carbonyl Compounds
The reduction of α,β-unsaturated carbonyl compounds may be carried out so that only one of
the π bonds is reduced – to give the allyl alcohol (reduction of the carbonyl group) or the
saturated carbonyl compound (the alkene double bond is reduced) – or so that both π bonds are
reduced (to give the saturated alcohol). The selective reduction of conjugated carbonyl systems
has been a fruitful area of research for many chemists, and as a result of their work we can now
choose which of these outcomes we actually want.
With the strongly nucleophilic complex metal hydrides, the allylic alcohol is usually the
predominant product – but not always. Sodium borohydride, in particular, reduces conjugated
carbonyl compounds only slowly, and the major product is frequently the saturated alcohol or
the saturated carbonyl compound; even lithium aluminum hydride frequently produces the
saturated alcohol. However, if sodium borohydride is used in the presence of cerium (III), the
reduction becomes highly selective, and only the allylic alcohol is produced. The same product is
obtained if an electrophilic metal hydride is used instead. Diisobutylaluminum hydride (DIBALH) is the most widely-used electrophilic reagent for reducing conjugated carbonyl compounds to
allyl alcohols, reacting almost exclusively by the 1,2-reduction pathway to give the allylic alcohol.
OH
OH
DIBAL-H
(96%)
O
OH
O
OH
NaBH4/CeCl3
(100%)
MeOH
The alkene π bond can be reduced by catalytic hydrogenation, or by dissolving metals (e.g.
the Birch reduction); dissolving metal reductions often result in the reduction of both π bonds.
Lithium in liquid ammonia reduces conjugated ketones to lithium enolate; in the presence of a
proton source, the enolate is protonated to the saturated ketone which is further reduced to the
saturated alcohol; without a proton source, the saturated ketone is isolated.
O
Li/NH3
OLi
ROH
O
Li/NH3
H3O
O
Li/NH3
OLi
H3O
OH
The Birch reduction of conjugated carbonyl compounds is an excellent method for the
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
regiospecific formation of a single lithium enolate. One feature of the Birch reduction of enones
is its strong stereochemical preference: when cyclohexenones are reduced, the β hydrogen atom
is added from the axial direction – even if this means that the less stable isomer of the product
will be produced.
Me
Me
OMe
Li/NH3/EtOH
Et2O
O
1) Li/NH3/Et2O
O
OMe
(65%)
O
H
O
(43%)
2) n-BuI
H
Problem 18.5. What will be the major organic product of the reduction of carvone, (S)-5isopropenyl-2-methyl-2-cyclohexenone, with each of the following reagents. Where
more than one stereoisomer may be formed, draw the structures of all stereoisomers
expected.
(a) Na/NH3/CH3CH2OH.
(c) H2/Pd-C.
(e) NaBH4/CeCl3/CH3OH.
(b) 1) Li/NH3/Et2O; 2) CH3CH2Br.
(d) DIBAL-H/hexane.
As was the case for the aldehydes and ketones, reduction of the alkene double bond of
conjugated carboxylic acid derivatives is best accomplished by catalytic hydrogenation, and
reduction of the carbonyl group by diisobutylaluminum hydride. The reduction of conjugated
esters by DIBAL-H is one of the best methods for the preparation of allyl alcohols.
CO2Me
DIBAL-H
CH2Cl2
OH
(92%)
The Robinson Annelation
Used alone, the Michael addition and aldol condensation reactions are powerful methods for
forming new carbon-carbon bonds in organic compounds. When combined in a single
procedure, however, they constitute one of the most powerful methods for the formation of
polycyclic compounds by of adding a ring to an existing compound – the Robinson annelation,
developed by British chemist Sir Robert Robinson. This reaction is a prototype of a whole class
of reactions where a new ring is added to an existing carbon skeleton; they are termed
annulations or annelations, and they provide a method for the construction of quite complex
molecules very quickly.
In the Robinson annelation, an α,β-unsaturated ketone is treated with an enolate anion or its
equivalent in the presence of a base. The first step of the reaction is the Michael addition of the
enolate to the enone to generate a new enolate. Under the reaction conditions, the enolate
formed in the Michael addition is in equilibrium with all the possible isomeric enolates. Of course,
since the intermediate formed has an enolate anion and a carbonyl group in the same molecule,
an intramolecular aldol addition may occur; however, only those aldol additions that result in the
formation of five- or six-membered rings are favored. The intermediate dicarbonyl compound in
the Robinson annelation may be isolated, but it is actually more common for the intramolecular
aldol condensation to be carried out before the final product – almost always the α,β-unsaturated
ketone – is isolated. Nucleophiles derived from active methylene compounds are probably used
more than any others for carrying out Robinson annelations, but enamines are also widely used.
687
DIFUNCTIONAL CARBONYL COMPOUNDS
Chapter 18 688
The course of the Robinson annelation is summarized in Figure 18.6.
R1
O
O
O
R3
R2
R2
R5
R5
••
R1
O
R2
R1
R4
R5
••
R1
R4
O R3 R3
R3
O
O
R2
R4
R3
R3
[shift of a proton;
generates a new enolate]
R5
R1
O
R2
R4
R3
R5
R5
O
O
R1
R2
R1
R4
R3
R3
••
O
R2
R4
O R3 R3
R3
Figure 18.6 The Robinson annelation.
Some typical examples of the Robinson annelation follow.
O
O
CH2=CH-CO-CH3
CH3
O
CH3
O
1)
KOH (cat.)/MeOH/Δ
O
CH3
N H /C6H6/Δ
(63-65%)
2) H3O
O
O
O
O
N H
N
1) CH2=CH-CO-CH3
TsOH/C6H6/Δ
Me3C
O
+
2) CH3CO2H/H2O/Δ
Me3C
CMe3
CMe3
Sample Problem 18.4 Draw the structure of the major conjugated ketone to be formed in
each of the following Robinson annelation reactions.
O
(c)
O
O
O
+
(a)
+
base/Δ
O
base/Δ
O
+
(b)
O
base/Δ
(d)
base/Δ
+
O
Answers:
O
(a)
O
(b)
O
(c)
O
(d)
Problem 18.6. Draw the structure of the major conjugated ketone to be formed in each
of the following Robinson annelation reactions.
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
(a)
O
O
O
+
base/Δ
O
(c)
O
(e)
O
O
+
CN
+
O
NMe2
base/Δ
O
base/Δ
+
(b)
base/Δ
+
(d)
O
O
base/Δ
base/Δ
+
(f)
O
Sir Robert Robinson (1886-1975). Robinson was educated at the University of Manchester, where
he took his Ph.D. in 1910 under W.H. Perkin, Jr. Robinson's first academic appointment was half a world
away from his home, at the University of Sydney, where he remained for three years before returning to
England to take up positions at the University of Manchester and then at the University of London. In
1930 he was appointed Waynflete Professor of Chemistry at the University of Oxford, a position he held
until his official retirement in 1955. Robinson's impact on chemistry was broad, but it was felt most deeply
in the area of natural products – especially plant pigments and alkaloids – and synthesis. He first proposed
the correct structure for strychnine, and he developed the most efficient method for the assembly of the
heterocyclic skeleton of the cocaine-type alkaloids. For his work in synthetic organic chemistry, Robinson
was awarded the 1947 Nobel Prize in Chemistry. A rival of Ingold in the development of electronic
theories of organic reaction mechanism, Robinson maintained a life-long feud with him over the claim of
priority in developing this important concept, and it is probable that he used his influence to prevent the
award of the Nobel Prize to Ingold. Robinson was knighted in 1939.
Reaction synopsis
Michael Addition
R
R
E
H–Nu
Nu
R
R
E
E = RC=O, ROC=O, C≡N, NO2, etc. (an electron-withdrawing group)
Reagents:
or
or
or
CN–, RS–, RO–, etc.
R2CuLi/THF, R2Cu(CN)Li2/THF, RCu•BF3, etc.
enolate anions, enamines, etc.
R2S(O)=CR2 (gives cyclopropanes); ROO– (gives epoxides).
Alkylation of Conjugated Carbonyl Compounds
(a) Kinetic alkylation
R
O
R
Base:
or
R
R
1) base
2) R′–X
R′
R
O
R
LDA/THF/-78°C, LICA/THF/-78°C, etc.
NaH/DMSO/Δ, etc.
(b) Thermodynamic alkylation
R
R
R
O
1) base
2) R′–X
Base: KOC(CH3)3/(CH3)3COH, etc.
R
R
R
O
R′
689
DIFUNCTIONAL CARBONYL COMPOUNDS
Chapter 18 690
Reduction of Conjugated Carbonyl Compounds
(a) To allyl alcohol:
R
R
O
R
Reagents:
R
[H]
R
OH
R
LiAlH4/Et2O/low temp./short time; DIBAL-H/hexane;
NaBH4/CeCl3/CH3OH; etc.
(b) To saturated ketone:
R
R
O
R
Reagents:
or
R
[H]
R
O
R
H2/Pd-C; etc.
Li/NH3 (no proton source); etc.
(c) To saturated alcohol:
R
R
R
Reagents:
or
R
[H]
O
R
R
OH
Li/NH3/ROH; etc.
NaBH4/MeOH; LiAlH4/Et2O/room temp./longer time
Robinson Annelation
R5
R1
O
R5
O
+
R2
R3
base
R4
R3
R1
O
R2
R4
R3 R3
base: RO–/ROH/Δ; NaH; etc.
enamines may be used instead of the enolate anion.
18.4 DICARBONYL COMPOUNDS, DINITRILES AND KETONITRILES.
When two carbonyl groups occur together in the same molecule, their chemistry depends on
their locations relative to each other. The same is true if one or both of the carbonyl groups is
replaced by a cyano group. If the two functional groups are separated by two or more carbon
atoms, they behave independently of each other – just like the chemistry we have already
discussed. Of course, this leaves two types of compounds whose chemistry is different from the
simple aldehydes, ketones or nitriles: those where the two functional groups are bonded directly
to each other, and those where they are separated by a single carbon atom.
Active methylene compounds
By far the most widely difunctional compounds of this type are those where the two
functional groups are separated by one carbon atom. When the two functional groups are both
carbonyl groups, these compounds are referred to as β-dicarbonyl compounds; if one of the
functional groups is a cyano group, the compounds are referred to as α-cyanocarbonyl
compounds, or β-ketonitriles; compounds in which both groups are cyano groups are referred
to as β-dinitriles, or, more commonly, as malononitriles.
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
Because the carbonyl group and the cyano group both stabilize a carbanion at the α carbon,
the position between the two functional groups should be especially acidic. The experimental
data that confirm this prediction are collected in Table 12.3: the pKa's of β-diketones and
malononitrile derivatives are in the range 9-12 – much less than the pKa's of simple aldehydes,
ketones and nitriles. This higher acidity of the hydrogens of the methylene group between the
functional groups has led to these compounds being called active methylene compounds, and
there are many such compounds that have been found useful in organic synthesis. Some typical
examples are gathered in Table 18.2.
Table 18.2 Some Typical Active Methylene Compounds
Structure
R–CO–CH2–CO–R
R–CO–CH2–CO–OR′
Generic Name
Specific Example
β-diketone
CH3–CO–CH2–CO–CH3
β-ketoester CH3–CO–CH2–CO–OCH3
Name
acetylacetone (acac)
methyl acetoacetate
(an acetoacetic ester)
RO–CO–CH2–CO–OR
β-diester CH3O–CO–CH2–CO–OCH3 dimethyl malonate
(a malonic ester)
R–CO–CH2–CHO
β-ketoaldehyde CH3–CO–CH2–CH=O
2-formylacetone
R–CO–CH2–C≡N
β-ketonitrile
CH3–CO–CH2–C≡N
2-cyanoacetone
N≡C–CH2–C≡N
malononitrile
The enolate anions of active methylene compounds are structurally very similar to the
dienolate anions discussed above. The HOMO of the enolate anion of active methylene
compounds has three lobes just like the HOMO of the dienolate anion, and there are three
canonical forms of the anion. In the enolate anion of an active methylene compound, however,
two of the canonical forms have the negative charge on an electronegative element rather than
on carbon. Both these canonical forms are major contributors to the resonance hybrid, with the
result that the enolate anions of active methylene compounds are strongly stabilized by
resonance.
X
Y
HOMO of enolate anion; X and Y are electronegative elements (O, N, etc.)
O
R1
O
O
R2
R1
major
O
••
O
R2
R1
minor
O
R2
major
The enolate anions of active methylene compounds can be generated quantitatively by bases
such as alkoxide anions, RO–, and they are exceptionally useful carbon nucleophiles which
participate in alkylation reactions, Michael additions, and aldol condensations.
CH3
K 2CO3/CH3I
O
O
(75-77%)
acetone/Δ
O
O
CN
1) NaH (excess)/DMSO
C6H5CH2
CN
2) C6H5CH2Cl (2 eq.)
C6H5CH2
CN
(75%)
CN
691
DIFUNCTIONAL CARBONYL COMPOUNDS
Chapter 18 692
O
O
CH3
O
+
KOH (cat. amount)
CH3
O
MeOH/Δ
O
O
α-Hydroxymethylene compounds.
Where one of the functional groups is an aldehyde group, the compound may be called an αformyl derivative. However, the enol content of these aldehydes is extremely high indeed, so
that α-formylketones, for example, actually exist as α-(hydroxymethylene)ketones. The
hydroxymethylene group has been used by organic chemists in two ways in synthesis: as an
activating group in alkylations (i.e. to ensure alkylation at one of the two methylene groups of a
ketone), and as a blocking group in alkylations (to prevent alkylation at one of the α carbons of
a ketone).
The introduction of a formyl group into a ketone is fairly straightforward. When a carbonyl
compound is heated with a formate ester in the presence of at least one equivalent of an alkoxide
anion base, the α-(hydroxymethylene)ketone is formed. The removal of the added group
(decarbonylation) is equally simple; it can be effected by simply warming the compound with
an aqueous base such as sodium hydroxide (Figure 18.7). If there is a choice between a
methylene group (CH2) and a methine group (CH), the formyl group is introduced on the
methylene side.
O
O
O
H–CO–OR/RO
ROH/Δ
R1
R2
OH
R4 OH/H
CHO
R1
R2
R1
H3O
R2
OR4
O
/Δ
R1
R2
1) base
2) R3–X
1) base
2) R3–X
KOH/H2O/Δ
O
R1
R3
OR4
O
CHO
R2
R3
R1
R2
Figure 18.7 The synthesis and reactions of α-(hydroxymethylene)ketones.
If an α-hydroxymethylene carbonyl compound is heated with an alcohol in the presence of
acid, it is converted to the corresponding enol ether. Since the enol ether has no hydrogens α to
the carbonyl group, it cannot form an enolate anion on the side that the hydroxymethylene
group is added to the original carbonyl compound – that α carbon is blocked. The blocking
group may be removed by first hydrolyzing the enol ether with dilute acid, and then
decarbonylating the hydroxymethylene compound formed. These transformations, also, are
summarized in Figure 18.7.
α-Cyanoketones: the Thorpe and Thorpe-Ziegler condensations
The reaction between a nitrile and an alkoxide base leads to the formation of a β-iminonitrile
from which an α-cyanoketone may be obtained by mild acid hydrolysis. This reaction is known
as the Thorpe reaction when intermolecular, and the Thorpe-Ziegler reaction when
intramolecular. The Thorpe-Ziegler reaction is especially useful in the formation of five- to eightmembered rings and for rings with more than thirteen members, although it fails for nine- to
twelve-membered rings.
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
H
CN
H
CN
1) NaH/DMSO/90-100°C
CN
2) H2O
3) HCl/H2O
H
O
H
Sample Problem 18.5. Draw the structures of all of the compounds formed when
2-methyl-3-pentanone is treated with the following sequence of reagents.
1) HCO2CH3/CH3O–/CH3OH/Δ; then H3O+ .2) CH3(CH2)3OH/TsOH/C6H6/Δ.
3) KOC(CH3)3/CH3CH2Br.
4) H2SO4/H2O.
5) K2CO3/H2O/Δ.
Answer:
OH
O 1)
OBu
2)
O
OBu
3)
O
O
OH
4)
5)
O
O
Problem 18.7.
Draw the structures of all of the compounds formed when
2-methylcyclohexanone is treated with the following sequence of reagents.
1) HCO2CH3/CH3O–/CH3OH/Δ; then H3O+ .2) CH3(CH2)3OH/TsOH/C6H6/Δ.
3) KOC(CH3)3/CH3)2CHBr.
4) H2SO4/H2O.
5) K2CO3/H2O/Δ.
Compare the structure of the final product from this reaction sequence with the product
formed by treating the same ketone with the following sequence:
1) LDA/THF/-78°C.
2) CH3CH2Br.
Problem 18.8. Draw the structures of all of the compounds formed when heptanedinitrile
is treated with the following sequence of reagents.
1) NaH/DMSO/100°C; then HCl/H2O.
2) NaH/CH3CH2I/DMF.
Reaction synopsis
α-Hydroxymethylene Carbonyl Compounds
O
HCO2R/RO–/Δ
R
HO
O
H
O
K 2CO3/H2O/Δ
R
R
R
R
R
Formylketones exist predominantly in the enol (hydroxymethyleneketone) form.
The hydroxymethylene group is added under strongly basic anhydrous conditions, and removed under
aqueous conditions.
Alkoxymethylene Blocking Group
HO
O
H
R′O
R
R′OH/H
O
H
R
H3O
R
R
HO
O
H
R
R
The blocking group is formed and hydrolyzed under acidic conditions; α-alkoxymethylenecarbonyl
compounds lack an acidic hydrogen on the side of the alkoxymethylene substituent.
Thorpe and Thorpe-Ziegler Condensation
693
DIFUNCTIONAL CARBONYL COMPOUNDS
Chapter 18 694
R
1) base
CN
2) H3O
O
R
R
CN
base: RO–/ROH/Δ; NaH; etc.
May be used to form cyclic compounds with up to 8 members in the ring.
18.5 THE ACETOACETIC ESTER AND MALONIC ESTER SYNTHESES:
DECARBOXYLATION OF β-KETOACIDS AND β-DIACIDS.
Most carboxylic acids are quite stable to heat, and the reaction conditions required to remove
the functional group, a reaction known as decarboxylation, are usually quite extreme.
However, the presence of the carbonyl group in a β-ketoacid activates the acid towards loss of
the carboxyl group, and most β-ketoacids can be decarboxylated at temperatures under 200°C.
One proposed mechanism for this reaction is shown in Figure 18.8.
O
H
O
R
O
O
H
R
R R
‡
O
O
H
R
R
O
R R
+
R
O
O
C
O
R
H
R R
Figure 18.8 The cyclic mechanism for decarboxylation of β-ketoacids and β-diacids involves the formation
of an enol through a six-membered cyclic transition state.
This mechanism predicts that the initial product of the decarboxylation reaction will be the
enol tautomer of the carbonyl compound produced. Experimental evidence for the formation of
an enol intermediate has come from several different studies. Thus, although the decarboxylation
of β-ketoacids which can generate an intermediate enol occurs quite readily, when one attempts
to decarboxylate β-ketoacids which cannot give an intermediate enol, the reaction fails. It has
also been observed that the decarboxylation occurs more easily as the enol that is formed
becomes more substituted. When the β-dicarbonyl compound has one or more substituents at
the α carbon, the decarboxylation occurs at temperatures near 100°C, so decarboxylation occurs
simply on boiling an aqueous solution of the β-ketoacid or the β-diacid.
O
O
Δ
CO2H
CO2H
O
CH3
O
CH3
CH3
CH3
CO2H
HO2C
CO2H
Δ
HO2C
CO2H
CO2H
The decarboxylation of β-ketoacids and malonic acids is of particular importance in biological systems.
In order to convert sugar to fat, for example, the body carries out what are essentially a series of Claisen
condensations and reductions. However, in order to avoid the strongly basic conditions needed by the
Claisen condensation, the living cell uses the decarboxylation of a malonic acid derivative to generate the
enol (or enolate) in close proximity to the carboxylic acid derivative (a thioester) that acts as the
electrophilic partner in the reaction.
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
RS
RS
CO2
O
+
RS
O
R′
RS
O
R′
O
O
Acetoacetic and malonic ester syntheses
Much of the chemistry of the β-dicarbonyl compounds was elucidated by the German chemist
Johannes Wislicenus (the "reputable chemist" referred to by Kolbe in his diatribe against van't
Hoff's tetrahedral carbon monograph). Wislicenus demonstrated that the two hydrogen atoms of
the methylene group between the carbonyl groups of ethyl acetoacetate could be replaced by
alkyl groups. When one couples the ease of replacing these methylene hydrogens with alkyl
groups and the easy decarboxylation of the corresponding β-ketoacids, this sequence of reactions
provides a method for the synthesis of ketones from simpler precursors that is known as the
acetoacetic ester synthesis. When the acetoacetic ester is replaced by a malonic ester, the same
chemistry can be carried out, but the final product is now a carboxylic acid instead of a ketone
and the reaction sequence is called the malonic ester synthesis. Some typical examples of the
acetoacetic ester synthesis of ketones and the malonic ester synthesis of carboxylic acids are
shown below.
O
O
1) NaEt/EtOH
2) PrBr/Δ
CO2Et
CO2Et
1) NaOEt/EtOH
2) BuBr/Δ
CO2Et
CO2Et
C4H9
CO2Et
O
1) KOH/H2O/EtOH/Δ
CO2Et
2) H2SO4/H2O/Δ
1) KOH/H2O/EtOH/Δ
CO2H
C4H9
2) H2SO4/H2O/Δ
The alkylation of acetoacetic ester enolates often gives substantial amounts of the O-alkylated
product as well as the expected C-alkylated product, and the exact amounts of each depend on
the solvent, the base, and the alkyl halide used. Some typical results are summarized in Table
18.3. This tendency to give the O-alkylated product is much less dominant with malonic esters,
and most syntheses involving β-dicarbonyl compounds are now carried out using β-diesters
wherever possible.
Table 18.3 The Regiochemistry of Alkylation of β-Ketoesters
O
O
CO2Et
+
X
K 2CO3/solvent
100°C
CO2Et
X
Cl
Cl
Cl
Cl
Br
I
solvent
acetone
acetonitrile
DMSO
DMF
DMF
DMF
+
CO2Et
O
CO2Et
Product Composition
90%
10%
81%
19%
53%
47%
54%
46%
67%
33%
>99%
<1%
Perhaps the most famous example of this problem dates from 1880, when William Henry
Perkin Jr. announced to his mentor, Adolf von Baeyer, that he had achieved the first synthesis of
a cyclobutane derivative. Baeyer was so excited that he immediately notified the scientific world
of this discovery, only to have Perkin find out three years later that the compound he had made
695
DIFUNCTIONAL CARBONYL COMPOUNDS
Chapter 18 696
did not have a four-membered ring at all! A year later, Perkin used diethyl malonate instead of
ethyl acetoacetate, and he did produce a four-membered ring. In the meantime, Markovnikov
had prepared the world's first authentic synthetic cyclobutane derivative (albeit in impure state).
CO2Et
CO2Et
NaOEt/EtOH
Br(CH2)3Br/Δ
CO2Et
1) KOH/H2O/Δ
CO2Et
2) H2SO4/H2O/Δ
CO2H
In addition to alkylation, the enolate anions of β-dicarbonyl compounds serve as excellent
nucleophiles for conjugate addition reactions. In fact, it was the addition of the sodium salts of
diethyl malonate and of ethyl acetoacetate to α,β-unsaturated esters that were the subject of
Michael's first paper describing what we now call the Michael addition. The enolate anions of βketoesters are also used as the initiating nucleophiles for the Robinson annelation reaction, as
shown in some of the examples that follow.
CO2Et
O
NaOEt (cat.)
EtOH/-10°C
+
CO2Et
CO2Et
O
CO2Et
CO2Et
CO2Et
+
O
CO2Et
Et3N/C6H6/25°C
O
(71%)
O
base/Δ
O
O
O
1) NaH
2) H3O
CO2Et
O
H
O
O
CO2Et
Problem 18.9. Each of the following carboxylic acids may be prepared from diethyl
malonate. Give a sequence of reactions which can be used to prepare them.
(a) heptanoic acid.
(c) 3-cyclohexylpropanoic acid.
(e) cyclopentanecarboxylic acid.
(g) 2-methylbutanoic acid.
(i) 4,4-dimethylcyclohexanecarboxylic acid.
(b) 4,4-dimethylpentanoic acid
(d) 4-pentenoic acid.
(f) 2-propylbutanoic acid.
(h) 2-ethyl-4-pentenoic acid.
(j) 5-methyl-4-hexenoic acid.
Problem 18.10. Perkin's first report of the preparation of a four-membered ring involved
the reaction between ethyl acetoacetate, 1,3-dibromopropane, and sodium ethoxide in
anhydrous ethanol. The final product possessed an ester group, and had the molecular
formula expected for the cyclobutane product. What is the structure of the cyclobutane
product which Perkin expected? What is the most probable structure of the compound
he actually obtained? What is the structure of the carboxylic acid which Perkin
expected from hydrolysis of the initial product? Based on the structure you have
written, would the product he actually obtained give a carboxylic acid with the same
molecular formula as the one expected from hydrolysis of the expected β-ketoester?
Problem 18.11. Any attempt to prepare ethyl 3-methyl-3-hydroxybutanoate by adding
one equivalent of methylmagnesium bromide to ethyl acetoacetate fails, even though
the ketone carbonyl group should be more reactive towards the organometallic reagent.
What reaction actually occurs on the addition of one equivalent of methylmagnesium
bromide to ethyl acetoacetate, and what product is actually formed? How would you
obtain evidence to support your answer?
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
Problem 18.12. Draw the structure of the major organic product expected from each of
the following reactions.
CO2Me
(a)
CO2Me
O
CO2Me
O
CO2Me
base
+
base
+
(b)
CO2Me
O
(c)
CO2Me
base
+
CO2Me
base
+
(d)
CO2Me
O
Reaction synopsis
Decarboxylation of β-Ketoacids and β-Diacids
O
OH
CO2H
G
R′
Δ
O
R′
G
R′
R′
G
R′
R′
Acetoacetic Ester Synthesis of Ketones
O
O
CO2R
O
1) base
2) R′X
CO2R
1) hydrolysis
2) Δ
R′
R′
Malonic Ester Synthesis of Carboxylic Acids
RO2C
CO2R
1) base
2) R′X
RO2C
CO2R
R′
CO2H
1) hydrolysis
2) Δ
R′
18.6 SUMMARY
The presence of two functional groups in close proximity affects the chemistry of both. When
an α-haloketone is treated with base, the product is a carboxylic acid derivative where one of the
α carbons of the haloketone has rearranged to the other α carbon. When the base is hydroxide
ion, the product is a carboxylate anion; when the base is an alkoxide ion, the product is the ester.
A special example of the reaction between an α-haloketone with a nucleophilic base is the
haloform reaction of methyl ketones, which gives the carboxylic acid with one less carbon atom
and the haloform.
Conjugated carbonyl compounds react with nucleophiles by 1,2-addition or by 1,4-addition.
Conjugated aldehydes usually give 1,2-adducts; conjugated esters and nitriles give 1,4-adducts
except with very strong nucleophiles (e.g. organolithium reagents). Conjugated ketones react
with nucleophiles that add reversibly to saturated ketones to give the 1,4-adduct as the major
product under basic conditions, and the 1,2-adduct under conditions of acid catalysis.
Organocuprates are especially important nucleophiles that add 1,4- to conjugated carbonyl
compounds; this reaction serves as an important method for forming carbon-carbon bonds. The
influence of the nucleophile on the course of additions is shown by sulfur ylides: sulfonium ylides
697
DIFUNCTIONAL CARBONYL COMPOUNDS
Chapter 18 698
convert conjugated enones to allylic epoxides; sulfoxonium ylides convert conjugated enones into
cyclopropyl ketones.
A sequence of Michael addition and intramolecular aldol condensation may be used to fuse a
new six-membered ring onto an existing carbonyl compound or enamine. The product of this
sequence, called the Robinson annelation, is a cyclohexenone.
Reduction of conjugated carbonyl compounds can give the saturated alcohol, the allylic
alcohol, or the saturated carbonyl compound depending on the reducing agent. Catalytic
hydrogenation over palladium catalysts or Birch reduction in the absence of a proton source give
the saturated carbonyl compound from conjugated ketones. Reduction of conjugated ketones or
esters with DIBAL-H gives the corresponding allylic alcohol; reduction of conjugated ketones
with sodium borohydride in the presence of cerium chloride also gives the allylic alcohol. Birch
reduction of conjugated ketones in the presence of a proton source saturates both π bonds to
give the saturated alcohol.
The α protons of β−dicarbonyl compounds are especially acidic due to the presence of two
carbonyl groups and the strong resonance stabilization of the conjugate base. These compounds
may be alkylated using relatively weak bases such as alkoxides to generate the enolate anion.
Free β-ketoacids or β-diacids both undergo ready decarboxylation on heating above 100°C; the
decarboxylation of β-ketoacids allows one to prepare α-branched ketones from an acetoacetic
ester by a sequence of alkylation, hydrolysis and decarboxylation. The same sequence using a
malonic ester as the starting compound can be used to prepare α-branched carboxylic acids.
18.7 GLOSSARY OF IMPORTANT TERMS
Acetoacetic ester synthesis – the synthesis of ketones by sequential alkylation of
acetoacetic ester followed by hydrolysis of the ester and decarboxylation of the resultant βketoacid.
Conjugate Addition – The 1,4-addition of nucleophiles to an α,β-unsaturated carbonyl
compound. Also known as Michael addition.
Decarboxylation – loss of carbon dioxide from a carboxylic acid. Particularly facile in βketoacids and β-diacids.
Favorskii Rearrangement – The reaction of an α-haloketone with a base to give an acid or
an ester by rearrangement of an alkyl group from the carbonyl carbon to the α carbon. A
cyclopropanone intermediate is implicated in most Favorskii rearrangements.
Haloform Reaction – The reaction of a methyl ketone with base and a halogen gives the
carboxylic acid with one carbon atom less than the methyl ketone. The methyl group of the
ketone is converted to the trihalomethane (the haloform).
Malonic ester synthesis – the synthesis of ketones by sequential alkylation of malonic ester
followed by hydrolysis of the ester and decarboxylation of the resultant β-diacid.
Michael Addition – The 1,4-addition of nucleophiles to an α,β-unsaturated carbonyl
compound. Also known as conjugate addition.
Robinson Annelation – Fusion of a new cyclohexenone ring onto an existing ketone or
ketone equivalent (e.g. enamine) by treatment of an enolate anion of enamine with an α,βunsaturated ketone and base.
18.8 ADDITIONAL PROBLEMS
18.13. Draw the structure of the major organic products expected from the reactions of each
of the compounds in the first list below with each of the reagents in the second list below.
If no reaction should occur, write "N/R." Where appropriate, specify the stereochemistry
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
of the major stereoisomer.
Compounds:
(1) 2-cyclohexenone
(3) R-4-tert-butyl-2-cyclohexenone
(5) E-2-butenenitrile
(2) 4-methyl-3-penten-2-one
(4) methyl 3-methyl-2-pentenoate
(6) 2-methyl-2-hexenal
(a) 1) DIBAL-H/hexane/0°C; 2) HCl/H2O.
(b) KCN/CH3OH.
(c) 1) CH3CH2CH2Li/THF; 2) H3O+ .
(d) lithium dicyclopentylcuprate.
(e) 1) LICA/THF/-78°C; 2) CD3I.
(f) HOCH2CH2OH/TsOH/C6H6/Δ.
(g) LiAlH4/Et2O/35°C/24 h.
(h) Li/NH3/CH3CH2OH.
(i) 1) HCO2CH3/CH3ONa/CH3OH/Δ; 2) CH3(CH2)3OH/TsOH/C6H6/Δ.
18.14. The intramolecular aldol condensation to give a cyclic product fails if the ring has eight
members, but the Thorpe-Ziegler condensation succeeds. Neither reaction can be used to
form rings with ten members. Suggest a reasonable explanation for these observations.
18.15. Write equations for the reaction(s) involved in the preparation of each of the following
compounds from the starting material given. Where there is more than one possible
answer, give at least two answers.
O
?
(a)
(b)
H
(c)
?
(d)
O
H
O
H
O
OH
Me
?
(e)
(f)
NH2
H
H
N H
O
H
OH
O
?
O
H
H
(g)
CHO
H
?
O
HO
?
O
?
OH
O
H
(h)
?
O
O
18.16. Draw the structure of the intermediate products formed and the final product when
cyclohexanone is subjected to each of the following sequences of reagents.
(a) 1) Br2/CH3CO2H; 2) KOCH3/CH3OH/Δ.
(b) 1) LDA/THF/-78°C; 2) CH3CH2Br; 3) HCO2CH2CH3/NaOCH2CH3/CH3CH2OH/Δ;
4) CH2=CH-COCH3; 5) K2CO3/H2O/Δ.
(c) 1) LDA/THF/-78°C; 2) (CH3)2CH-I; 3) HCO2CH3/NaOCH3/CH3OH/Δ;
4) CH3(CH2)5OH/TsOH/C6H6/Δ; 5) LDA/THF/-78°C; 6) O=CH-CH=CH2.
699
DIFUNCTIONAL CARBONYL COMPOUNDS
Chapter 18 700
(d) 1) HCO2CH3/NaOCH3/CH3OH/Δ; 2) CH3-CH=CH-COCH3; 3) K2CO3/H2O/Δ;
4) Li/NH3; 5) H3O+ .
(e) 1) (CH2)4NH/TsOH/Δ; 2) CH2=CH-COCH3; 3) HSCH2CH2CH2SH/BF3; 3) Li/NH3;
4) H2/Pd-C.
(f) 1) LDA/THF/-78°C; 2) cyclopentyl bromide; 3) LDA/THF/-78°C; 4) CH3I;
5) m-CPBA/CH2Cl2.
18.17. When 2-cyclohexenone is treated with sodium ethoxide in D2O, the compound below
is obtained. When 3-cyclohexenone is treated under the same conditions, the same
product is obtained. Write a mechanism for the exchange reaction which is consistent with
these observations. [Note that one cannot exchange hydrogen atoms directly bonded to
an sp2-hybridized carbon atom.]
O
O
D
NaOEt
D2O
O
D
D
NaOEt
D2O
D D
18.18. Draw the structure of the major organic compound isolated after each of the
compounds in the first list below is treated with each of the reagents in the second list
below.
O
CO2H
(a)
N
(b)
N
(c)
O
(e)
O
N
O
(d)
O
O
CO2CH3
O
O
(f)
(g)
NH
(h)
N
CN
Reagents:
(a) 1) CH3Li; then 2) HCl/H2O.
(b) 1) LiAlH4/Et2O; then 2) HCl/H2O
(c) 1) NaBH4/(CH3OCH2CH2)2O; then 2) HCl/H2O.
(d) 1) CH3MgBr/Et2O; then 2) HCl/H2O.
(e) 1) LiCu(CH3)2/Et2O; then 2) HCl/H2O.
(f) 1) (C4H9)2Cd; then 2) HCl/H2O.
(g) H2/Pd-C/CH3CH2OH.
(g) LiOC(CH3)=CH2/THF/-78°C.
18.19. Meldrum's acid is a valuable synthetic intermediate that is often used in place of
diethyl malonate because of its ease of hydrolysis prior to decarboxylation. What
structural feature of Meldrum's acid should make it much easier to hydrolyze under acidic
conditions than diethyl malonate?
O
O
O
O
Meldrum's acid
Chapter 18
DIFUNCTIONAL CARBONYL COMPOUNDS
18.20. The δ-ketoester formed during Michael addition reactions of enolates to conjugated
esters may undergo intramolecular condensation to give a β-diketone if there is no proton
source present in the reaction mixture to trap the intermediate enolate anion. Write a
mechanism to account for the formation of the two products below.
O
O
O
CH2=CH-CO2Et
1) NaOEt
NaOEt
2) H3O
CO2Et
O
18.21. Draw the missing structures in each of the following sequences of reactions.
1) O3/CH2Cl2/-78°C
(a)
KOH/EtOH
A
2) (CH3)2S
NH2NH2/KOH
B
HOCH2CH2OH
Δ
(C10H16)
C
(C10H16)
O
CO2CH3
1) NaOMe/MeOH/Δ
2) CH3–CH=CH–CO2Me
CO2CH3
E
Cl
(C6H9O3Na)
CO2Et
(c)
D
NaOEt/EtOH
(b)
F
NaOH/H2O/Δ
(C10H16O3)
G
(C10H16O6)
(C7H12O)
BuSNa/DMSO
H2O/Δ
H
(C8H14O4)
pig liver
esterase
J
SiO2/CH2Cl2
(C7H10O2)
I
BH3•SMe2/THF
(C8H14O3)
CO2CH3
CO2H
18.22. The reaction between the epoxyketone below and a strong base such as potassium
ethoxide gives the ring-contracted ester whose structure is shown below. Write a
mechanism that is consistent with the formation of this ester.
O
O
EtO2C
KOEt/EtOH
O
O
701