Problem Set 8, Chapter 22
Due: April 11, 2005
Enols and Enolates
The base-mediated condensation of esters
to form β-ketoesters has had an interesting history.
Although the reaction often bears the name of
Ludwig
Claisen (1853-1930), who explored
the scope of this reaction (1887) and related ones, he did
not discover it. In 1863, Geuther discovered that sodium
reacts with ethyl acetate to liberate hydrogen and generate
a new compound C6H9NaO3.
Acidification of the sodium salt afforded "ethyl diacetic
acid". The sodium compound reacted with alkyl halides to
form a series of alkyl ethers. Consequently, Geuther
formulated ethyl diacetic acid as having the the enolic
structure
CH3CH(OH)=CHCO2C2H5. Claisen found vindication in his
mechanism because it explained why diethyl oxalate
successfully condensed with ethyl butyrate but not with
ethyl isobutyrate. Simply put, ethyl isobutyrate only had
one hydrogen available and not the two minimally required by
his mechanism. Dieckmann (1900) demonstrated that the
problem was not that ethyl isobutyrate had only one hydrogen
available but rather that the product formed with diethyl
oxalate was formed reversibly. In subsequent papers, Claisen
would expand the scope of these condensation reactions.
At about the same time, Frankland (of valence
fame) and Duppa (1866) produced the same sodium salt by the
same method. They proposed not only the formation of the the
monosodium salt of ethyl acetate but also its disodium salt
because they were able to isolate products of dialkylation
on carbon. The formulation of Geuther's ethyl diacetic acid
as a ketonic substance by Frankland led to acceptance of his
views and a name change to acetoacetic ester. [You can
see their paper here.
Notice that they drew structures in the form of the then
prevalent type theory. In this paper the Gay-Lussac method
for determining the vapor density of a volatile compound was
employed. A translation of Biot's description of the method
and original diagrams of the apparatus are here.]
By 1877, Wislicenus demonstrated that there were no dianions
in the process and that the dialkylation process was
stepwise. In Claisen's 1887 paper he was able to show that
sodium ethoxide and not sodium was the true condensing
agent. Moreover, he claimed that the same sodio orthoester,
PhC(OCH2Ph)(OCH3)(ONa), was formed
from benzyl benzoate and sodium methoxide or methyl benzoate
and sodium benzylate. He proposed the following "mechanism",
albeit from the "lasso school", for the formation of the
sodium salt of acetoacetic ester.
Nef (1897) suggested that Claisen's sodio orthoester could
lose ethanol to form what we would call the enolate of ethyl
acetate. This species could then react, in some unspecified
way, with ethyl acetate to lead to the sodium salt of
acetoacetic ester. On the other hand, Michael correctly
pointed out that there was no evidence that Claisen's sodio
orthoester even existed. Lapworth (1902) formulated the
correct mechanism for the acetoacetic ester condensation.
The controversy over whether acetoacetic ester existed in
the keto or enol form led to the concept of tautomerism. In
fact, acetoacetic acid exists in both forms. The tautomeric
structures are readily seen in the 13C NMR
spectrum of acetoacetic
ester. Knorr (1911) separated the
enol and keto forms of acetoacetic ester. Source: J. B.
Cohen, Organic Chemistry (1907)
1. Provide the conditions necessary to
complete each of the following transformations. All
reagents, solvents, and additional sources of carbon are
available to you. 2. Capsaicin
(1) is the hot, hot, hot in chili peppers. In spite
of what the link claims, capsaicin is not an
alkaloid. A reasonable synthesis of capsaicin
requires carboxylic acid 7. Importantly, the double
bond must be in the correct position in the chain and of the
(E)-configuration, i.e., trans. Allylic alcohol
2 provides a convenient starting material. One pathway to 7 is 2
--> 4 --> 5 --> 7. The
formation of bromide 4 occurs via an SN1
reaction. d) Why is little, if any, of the
(Z)-bromide formed? [Hint: Compare the two
allyl cations.] e) Show how the malonic ester
synthesis can be used for the conversion 4
--> 5. An alternative, efficient route
from 2 --> 5 involves the reaction of
allylic alcohol 2 with ethyl orthoformate in the
presense of an acid catalyst in refluxing (boiling)
toluene. Intermediate 3 is formed along
with ethanol. In large scale reactions, toluene is often
distilled from the reaction vessel? h) Write an acid-catalyzed mechanism
for the formation of 3 from 2. i) How do you know that formation of a
cation from ethyl orthoacetate is more efficient than the
formation of a cation from the allylic alcohol 2?
Draw them and explain. [Hint: Note that the reaction
is efficient.] Intermediate 3 forms ester
5 by rearrangement (Johnson-Claisen). A C-O single
bond is broken as a C-C single bond is formed while two
double bonds move. The stereochemistry of this
rearrangement, i.e., (E)- over (Z)- double
bond, has been explained using conformational model
6. The chairlike transition state resembles the
ground state chair conformation of cyclohexane. Importantly,
transition state 6 illustrates the importance of
orbital overlap of the breaking, forming, and moving bonds
while structure 3 does not. l) Of the transition states
6a and 6b, which one leads to
ester 5? Explain and illustrate. m) What is the product of the
other transition state? n) Why is the transition
state leading to the (E)-isomer
preferred? The malonic ester synthesis can
be utilized again to homologate 5 -->
7 by the unit
-CH2CH2-. p) Prepare the benzylic amine
from vanillin that is required for the synthesis
of capsaicin. q) Synthesize
capsaicin. 3. Ludwig Claisen not only developed the
condensation reaction that bears his name but he also
uncovered the original Claisen rearrangement. [Note: It
is uncanny how eponomous reactions are always discovered or
developed by the person with the same name. How come J. Doe
didn't discover the Claisen rearrangement?] While
investigating the reaction of the anion of acetoacetic ester
with allyl bromide, he isolated two compounds of the same
formula, C9H14O3. Compound
A was unaffected upon distillation and was found to
be soluble in dilute aqueous NaOH. Compound B was
insoluble in dilute NaOH; it rearranged to compound A
upon distillation [i.e.; heat]. Aqueous acid
hydrolysis of A afforded unsaturated ketone C,
C6H10O. What are the structures
A-C? Explain and illustrate their
formation. 4. Provide the structures and mechanisms
for formation of the lettered compounds in each of the
problems below. 5. A search of the chemical literature
revealed that the conjugate "acid" of the sodium salt in
problem 4c above can be prepared as shown on the
right.
a) Why?
b) How can 2 be prepared
from isobutyraldehyde and acetylene?
c) Illustrate the
mechanism.
f) Would phenol be a weaker or
stronger catalyst than p-nitrophenol? Explain and
illustrate.
g) Why?
j) Use three curved arrows on
structure 3 to illustrate this process. [Note:
One direction of arrow motion is preferable to the other.
Explain.
k) Illustrate the
overlap.
o) Illustrate the
malonic ester synthesis.
a) Show how the reactant can be
prepared from malonic acid and phenol.
b) Provide a mechanism for the formation of the lactone.
[Note: Although we have not seen examples of F-C
reactions with esters, phenyl esters are more reactive
than alkyl esters. Notice that the reaction is being
conducted at temperatures well above what is necessary
for standard acyl chloride F-C reactions.]
c) Draw a tautomeric form of the lactone.
d) Is aqueous NaOH suitable for forming the sodium salt
of the lactone? Explain.