CHM 252 Organic Chemistry II
Experiment #2, Spring 2008
The Aldol Condensation
Introduction
The aldol condensation is a term used to describe any number of reactions involving an enolate
and a carbonyl compound. Other examples of reactions involving similar types of chemistry
include:
(a) the Claisen condensation
(b) the Claisen-Schmidt condensation
(c) the Knoevenagel condensation
(d) the Dieckmann condensation
(e) the malonic ester synthesis
(f) the acetoacetic ester synthesis
(g) the Michael reaction
The general reaction involves: (a) the removal of an acidic -hydrogen from one carbonyl
containing molecule generating the enolate; (b) attack of the slightly positive carbon of a second
carbonyl containing molecule by the carbanion of the enolate; (c) eventual loss of water by the hydroxy carbonyl compound to yield the ultimate ,-unsaturated carbonyl product. The general
reaction scheme is shown below.
a c i dic -hydroge ns
e nol at e
O
R
H
C
O
C
OH
R'
-
R
C
H
C
R'
H
O
O
R
C
C
C
R'
R2
R3
R
R
O
C
C
C
H
R3
H
R
OH -
O
R
OH
C
C
C
H
R3
-hydroxy (a l dol ) produc t
R2
-H 2 O
R
-
O
O
R
C
C
C
R2
R3
, -unsa t ura t e d c a rbonyl produc t
H
R2
O
H
This type of chemistry has been exploited extensively by both the synthetic chemist and
by enzymes in biological systems. In synthetic organic chemistry, these types of reactions have
been shown to be highly useful in the synthesis of complex natural products. Within the last
twenty years, much has been discovered about the synthetic utility of enolates. The primary
utility comes from the fact that given certain reagents and reaction conditions, the synthetic
chemist can utilize the reaction to form carbon-carbon bonds (here it is again!). In addition, these
reactions generally occur with a high degree of stereoselectivity. The stereoselective nature of
these reactions allows chemists to create various complex natural products that contain multiple
stereocenters. We can actually introduce those stereocenters into the molecule using enolate-type
chemistry! Therefore, enolate chemistry has a high degree of synthetic utility.
There are also many biological examples of "aldol-type" reactions. For example,
collagen, the most abundant protein in many vertebrates and invertebrates, provides strength to
bones, tendons, cartilage, and skin. This strength has been attributed to the extensive crosslinking of lysine residues. The first step in the cross-linking process is the conversion of two
lysine residues to aldehydes by an enzyme called lysyl oxidase. Once converted, the two
aldehydes undergo an aldol condensation to provide a covalent cross-link (new carbon-carbon
bond). Further cross-linking may occur (Michael reaction) in order to link together up to four
residues.
A second example of the involvement of aldol chemistry in biological systems occurs
during the second stage of glycolysis (metabolic pathway in living systems used to produce
modest amounts of ATP). During this stage, the six carbon sugar (fructose-1,6-diphosphate) is
split into two three carbon units (dihydroxyacetone phosphate and glyceraldehyde 3-phosphate)
by the enzyme aldolase (Refer to Biochemistry, Fourth Edition by Lubert Stryer, Chapter 19).
Basically what happens here is the REVERSE of an aldol condensation (a retro-aldol
condensation). Without this step the six carbon sugar could not be reduced to the necessary three
carbon unit for the production of ATP.
A final example can be found in the citric acid cycle. Citric acid is formed by a Claisentype condensation between oxaloacetate and acetyl coenzyme A. The acidic -hydrogen on
acetyl CoA is removed by the enzyme citrate synthetase. Once removed, the enolate can attack
the carbonyl of oxaloacetate to yield citryl CoA. Hydrolysis of this compound yields citric acid.
Objective
In this week's experiment, you will be synthesizing an addition product from the aldol
condensation of an unknown aldehyde and an unknown ketone. The product of the reaction is an
,-unsaturated ketone. You will have considerable control over how you go about performing
this experiment. I will give you general guidelines. The goal here is for you to determine the
identity of your product from proton and carbon NMR. Once you have identified your product,
you will need to determine both the reaction mechanism and the identities of your starting ketone
and aldehyde. You will be assigned ONE of the procedures shown below.
Procedure A (Monday Laboratory Students)
In a 125 mL Erlenmeyer flask, dissolve 50 mmol of the unknown ketone A in 25 mL of
diethyl ether. Add 45 mL of 0.1 M NaOH and cool the mixture in an ice bath for 5 minutes. Add
50 mmol of freshly distilled unknown aldehyde A. Cork the flask loosely and stir the solution
vigorously in a cold water bath for 45 minutes.
Filter the reaction mixture by vacuum filtration and thoroughly wash any solid on the
filter paper with 10 mL of ether. Save the solid and weigh it when it is dry. Shake the filtrate in a
separatory funnel in order to extract any residual product from the aqueous layer. Save the ether
layer and extract the remaining aqueous layer with an additional 15 mL portion of ether.
Combine ether layers and wash with saturated NaCl solution (25 mL). Dry the ether layer over
magnesium sulfate and evaporate the solvent in the hood under low heat.
Purify the residue by short path vacuum distillation with no cooling bath. Any unreacted
starting material and residual ether should distill below 100 ºC. The forerun should be disposed
of in the hood waste containers. Collect the distillate boiling above 100 ºC and cool until it
solidifies. Purify by recrystallization from ethanol-water. Once you have isolated the solid
product let it dry. Measure the mass for the final product you recrystallized. Prepare a sample for
NMR analysis in the usual fashion. You should acquire the 1H-NMR and I will collect the
following: 13C NMR, 13C DEPT-135, 1H-1H COSY, HMQC 1H-13C correlation.
Procedure B (Tuesday Laboratory Students)
In a 125 mL Erlenmeyer flask, dissolve 10 mmol of the unknown ketone A in 10 mL of
diethyl ether. Add 12 mL of 0.1 M NaOH and 6 drops of the phase-transfer catalyst,
tricaprylmethylammonium chloride (Aliquat 336). Cool the mixture in an ice bath for 5 minutes.
Add 2.0 mL of freshly distilled unknown aldehyde A. Cork the flask and shake the solution
vigorously for 15 minutes. Swirl it frequently in the ice bath to prevent pressure buildup. Let the
reaction stand at room temperature for 10-20 minutes.
Collect the product by vacuum filtration and wash it on the filter with diethyl ether. Pull
the vacuum for about 10 minutes to assist in drying. Recrystallize the product from 2-butanone,
using about 12 mL of solvent per gram of crude product. Wash the product on the filter with
ether. Measure the mass for the final product you recrystallized. Prepare a sample for NMR
analysis in the usual fashion. You should acquire the 1H-NMR and I will collect the following:
13
C NMR, 13C DEPT-135, 1H-1H COSY, HMQC 1H-13C correlation.
Laboratory Follow-up (LFU)
Due: Tuesday, April 22, 2008 by 5:00 pm
You should compose a short RESULTS/DISCUSSION-style report (limit 4 pages) in which you
summarize/discuss the outcomes from your aldol condensation experiment. The report should
include all spectra (attached) and a ChemDraw representation of the proposed product structure
(fully labeled). Be sure to label all of the protons and carbons and correlate them with the
appropriate peaks in your NMR spectra. Be sure to discuss how your data is consistent with
your proposed structure (story of elucidation). In addition, you should compare/contrast your
product with that of the other lab section (you’ll need to work up their data as well). You’ll likely
want to provide the complete mechanism of reaction that outlines the steps in the conversion of
the two carbonyl starting materials into your proposed products.