The Aldol Reaction

The Aldol
Reaction



Introduction-



Near the end of the discussion of
enolization there was an analysis
of the reactivity of hydroxide ion towards the carbonyl carbon
compared to the hydrogen a
to the carbonyl carbon in acetaldehyde. That analysis concluded
that addition to the carbonyl group was approximately 10,000 times
more likely than abstraction of an a-hydrogen.
But because addition of hydroxide ion to the carbonyl group is
readily reversible, it is a non-productive reaction.

While the abstraction of an
a-hydrogen is
also a reversible reaction, the enolate ion that is formed has an
alternative reaction pathway available to it- addition to the
carbonyl carbon of another acetaldehyde molecule. This is called
the aldol
reaction.
Figure 1 summarizes the process.

Figure
1



The Aldol Reaction
of Acetaldehyde





Note that the net effect of the aldol
reaction is to add the "components of" one molecule of
acetaldehyde to the carbonyl group of a second molecule of
acetaldehyde, the "components of" acetaldehyde being H and
HCOCH₂.

The aldol reaction of two aldehydes is of
limited synthetic utility. However, there are many "aldol-like"
reactions which involve the essential features described in Figure
1. Figure 2 highlights these features.

Figure
2



General Features of
the Aldol Reaction





The aldol reaction requires an aldehyde or
ketone that contains at least one a-hydrogen. The
a-carbon
becomes nucleophilic when it is deprotonated by a base. The
carbonyl
carbon is electrophilic. Coulomb's Law
brings these two oppositely charged species together to form a C-C
bond.

The R groups may be H, alkyl, or aryl. When
the R groups in one molecule are different than those in the
other, the reaction is called a crossed-aldol
reaction. The
ability to join different aldehydes and ketones together is what
give this process its synthetic value.

The word aldol is a common name for the
product of the reaction shown in Figure 1. It is a type of
compound called a b-hydroxyaldehyde.
Generally the word aldol is used to refer to any
b-hydroxyaldehyde
or b-hydroxyketone.



Exercise 1
Enter the letter of any compound
that does not meet the structural requirements for the aldol
condensation:



Exercise
2 Enter the letter of any
b-hydroxyaldehyde
or b-hydroxyketone
into the text field:



Exercise
3 Draw the structure of the aldol
that would be formed from the aldol condensation of each of the
following aldehydes and ketones.







Like other alcohols, b-hydroxyaldehydes
and b-hydroxyketones
undergo dehydration to produce alkenes. In fact, it is difficult
to isolate b-hydroxyaldehydes
and b-hydroxyketones
because they are very prone to dehydration.

Dehydration of
b-hydroxyaldehydes
and b-hydroxyketones



In order to isolate the product shown in
Figure 1, the reaction conditions must be mild; the temperature
must be kept low and the amount of acid used to protonate the
alkoxide ion intermediate must be carefully controlled. If too
much acid is added, or if the temperature is too high, the aldol
will dehydrate to form a conjugated
alkene as demonstrated in Figure 3.

Figure
3



Dehydration of a
b-hydroxyaldehyde





The conjugated alkene shown in Figure 3 is
also called an a,
b-unsaturated
aldehyde. This means that the double bond is between the carbon
atoms a and
b to the
carbonyl carbon. In this position the p orbitals of the double
bond may interact with those of the carbonyl group to form an
extended, i.e. delocalized, pi system. The delocalization of the
electrons in this pi system results in greater stabilization since
the electrons experience greater nuclear attraction. Figure 4
offers two perspectives of the orbital geometry that affords this
extra stabilization. The trans isomer was chosen
arbitrarily.

Figure
4



Orbital Alignment
in a,
b-unsaturated
Systems









Exercise
4 Draw the structure of the
a,b-unsaturated
aldehyde or ketone that would be formed by dehydration of each of
the aldol products you drew in Exercise 3.





Retrosynthetic
Analysis



For synthetic organic chemists it's
important to develop the ability to mentally "deconstruct" a
target structure into simpler molecules from which that target may
be made. The process of intellectual deconstruction is called
retrosynthetic
analysis. The focal point of such
endeavors is inevitably the functional group(s) within the target
molecule. In the case of a,b-unsaturated
aldehydes or ketones the functional group of interest is the C-C
double bond. Disconnecting these two carbons as animated in Figure
5 reveals the structures of the two components from which the
target molecule was prepared.

Figure
5



Take One Step
Back









Exercise
5 Each of the following compounds
was prepared by an aldol condensation followed by dehydration. In
each case, select the structure of the starting material from the
list of choices in the box below. Enter the appropriate letter
into the text field.





Exercise
6 Each of the following compounds
was prepared by a crossed aldol condensation followed by
dehydration. In each case, select the structures of the starting
materials from the list of choices in the box above. Enter the
letter of the compound that serves as the nucleophilic component
followed by that of the electrophilic component. For example, the
nucleophilic component used to prepare the first compound is A,
while the electrophilic component is F.









Examples



Treatment of acetone with base results in
the aldol reaction shown in Equation 1.



Experimentally reaction 1 is tricky to
perform. However, if the product is separated from the reaction
mixture as it is formed, it is possible to isolate the product in
over 70% yield.

Acetone participates in a crossed-aldol
reaction with furfural, an aldehyde produced from corn stalks, as
described by Equation 2, where the carbon-carbon bond that is
formed is highlighted in red.



An amazing aldol-type reaction was involved
in the total synthesis of ginkolide B, one of the active
components in extracts from the Ginko biloba tree. Equation
3 outlines this key step.



In this reaction the potentially
nucleophilic carbon is a
to the carbonyl group of an ester rather than a ketone or
aldehyde. Lithium diisopropylamide (LDA) was used to deprotonate
this carbon. The resulting enolate ion added to the carbonyl
carbon of the complex pentacyclic ketone to form the C-C bond
shown in red.

Equation 4 depicts an intramolecular
crossed-aldol reaction that constituted
the last step in a total synthesis of racemic progesterone.
Even though the reaction conditions were very mild, the
intermediate



b-hydroxyketone
underwent spontaneous dehydration to produce the
a,
b-unsaturated
ketone.

O=CHem
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