A Green Enantioselective Aldol Condensation for the Undergraduate Organic Laboratory

George D. Bennett
J. Chem Ed. Vol. 83 Nov 12 2006

Aldol condensation experiments offers an opportunity to emphasize its importance in the

concepts and the use of various techniques in organic chemistry since it offers high product yield,
and ease of purification and dehydration. Aldol condensation is the reaction between a ketone with
another ketone/aldehyde, usually in a basic environment. This utilizes techniques such as
extraction, polarimetry and spectroscopy. Conceptually, this also highlights the concept of
enantioselectivity.
Enantioselectivity is an important concept in the field of organic chemistry. Its pursuit has
been studied for several years due to its important in drug making. For this experiment, the
reaction is proline catalyzed reaction between acetone and isobutyraldehyd as shown below.

Large excess of acetone and Isobutyraldehyde was reacted in the presence of L-proline at
room temp and pressure. Acetone served as the starting reagent and the solvent to suppress for side
reactions. The formation of the product was slow appearing only after 24 hours, and at least 48
hours are needed to get appreciable yields. The product is then extracted by ether from the reaction
mixture. Its identity was then assessed using IR, 1H NMR, 13C NMR, and polarimetry.
The yield on the average was about 50-60%. On the other hand, NMR results showed that
there were no presence of unreacted aldehyde, dehydrated adduct, or proline. Meanwhile, the
polarimetry showed a major excess of the positive specific rotation with lit value of + 61.7º for an
excess of 96% for the (R)-enantiomer.

In this particular experiment, it also takes a look at the mimicry of the amine-based catalyst
to aldolase enzymes. Aldolase enzymes are biological enzymes which directly catalyzes the
reaction between two unmodified carbonyl compounds. There are two classes of aldolase enzymes.
Class I uses an amine-based mechanism, while class II aldolases use a zinc cofactor. The L-proline
is thought to mimic the Class I route. The proposed mechanism for this reaction is shown below.
It is proposed that the mechanism of the reaction involved an iminium precursor of the reactive
intermediate. During the addition of enamine to aldehyde, the rigidity of the enamine ring and the
H-bond between the enamine carboxylate and aldehyde oxygen made it possible for the reaction’s
enantioselectivity.
The reaction is considered green due to the non-requirement of inert atmosphere or extreme
conditions, using non-toxic reagents in the process. It also utilizes a catalyst that is renewable,
biodegradable and available that is used only in small amounts. The catalyst is also water-soluble
making it very easy to remove from the reaction mixture. However, due to its very slow reaction
time, this process is still not viable for industrial scale.