The Aldol Condensation PuzzleRevised January 2002

The Aldol Condensation is an extremely useful carbon-carbon bond forming reaction in organic chemistry. In this experiment, a mixed Aldol Condensation will be performed. This means that two different carbonyl compounds will be used, but only one, the ketone, will have α-hydrogens: the aldehyde will not have α-hydrogens. The overall reaction is shown below.

O

H

G

CC

C

RR

O

H

HH

H2 +

NaOH, H2O

ethanol

CC

CC

C

OH H

RRG G

Aldehyde Ketone Aldol Condensation Product

Some of these aldol products show cytotoxic and anti-tumor activities (see Dimmock, J. R., et al, J. Pharm. Sci. 1994, 83(6), 852-858).

If the aldehyde has acidic α-hydrogens, then it could react with itself. By choosing aldehydes without α-hydrogens, the aldehyde will react with the ketone. Although the ketone could do an Aldol Condensation with itself as well, it usually reacts much faster with the aldehyde (why?).

The carbon-carbon double bonds that are formed are usually in the configuration shown, the so-called "trans, trans" form. Trace amounts of the "cis, trans" and "cis, cis" probably also form, but these isomers are less likely to be solids, so they do not crystallize out of solution.

To make this lab a little more challenging, you will not know the identity of the aldehyde or ketone you are using. Instead, you will be assigned a coded aldehyde and ketone to react together. You will purify a small portion of the product by recrystallization, and determine the melting point. You will demonstrate the purity of your product by TLC, and then obtain the NMR spectrum of your product. From the NMR and melting point data, you should be able to deduce what aldehyde and ketone you started with.

The reaction produces several intermediates before the final product is produced. These are shown below. You can draw the arrows and supply the missing steps. The reaction is catalytic in hydroxide. The ethanol solvent serves to keep the intermediate structures in solution so that the final product can be formed.

1

CC

C

RR

O

H

HH

H+

ArC

O

H

ArC

CC

C

RR

OH OH

H

H

HAr

CC

CC

RR

O

H

H

H

ArC

O

H

ArC

CC

C

RR

OH

CAr

OH H

HArC

CC

C

RR

OH

CAr

H

4-ethylbenzaldehyde is not in the CRC Handbook or in the Merck Index. The physical constants you might want are given below.

Molecular weight: 134.18Density: 0.979Boiling Point: 221

General Procedure

In a 50 mL Erlenmeyer flask place in this order the ketone (0.5 mL), the aldehyde (2.0 mL), 95% ethanol (12 mL), and 2M aqueous sodium hydroxide (10 mL). Stir or shake the reaction mixture until no more precipitate is observed to form. Some reactions form precipitate almost immediately; others require several hours. If no precipitate has formed after 15 minutes, you have a slow-reacting mixture. You can either allow this sit until the next lab period, or heat the reaction mixture on the steam bath for about 15 minutes, then allow the reaction to cool, and see if crystals form. Magnetically stirring the reaction mixture also speeds up the rate of reaction.

Once crystallization is complete at room temperature, cool the reaction in an ice bath, and then collect the product by suction filtration. Wash the product consecutively with ice-cold, 5 mL portions of:

1. 95% ethanol,2. 5% acetic acid in 95% ethanol,3. 95% ethanol.

Recrystallize a small portion of your product from either 95% ethanol or toluene (whichever solvent works the best). Check the purity of your crude and recrystallized products by TLC. Dissolve tiny amounts of each in ethyl acetate in separate small test tubes, and spot each solution on a small silica gel TLC plate. Use toluene as a developing solvent, and visualize the plate with UV light to see the spots if needed. When you have demonstrated that your recrystallized product is pure, you can obtain the NMR spectrum of your product from your lab instructor.

2

Hints on interpreting your NMR spectrum.

A general structure of the Aldol product is shown below.

CC

CC

C

OHa Ha

RRG G

Hb

Hc

Hc

Hb

Hb

Hc

Hc

Hb

1. The alkene hydrogens, Ha, usually show up in the aromatic region of the spectrum, around 7.2-7.6 ppm. If your ketone is acetone, the R = H, and these hydrogens usually show up close to 7 ppm. This is due to the C=C being conjugated to the C=O. If R = H, it will couple with Ha with a large coupling constant, about 15-18 Hz.

2. The aromatic hydrogens, Hb, appear about 7.3 ppm. Hc, on the other hand, may appear between 6.7 and 7.3 ppm, depending upon what G is. Hb and Hc usually couple with each other, so each appears as a doublet. However, if Hb and Hc are very close to one another in chemical shift, the coupling patterns may be severely distorted. Ha may show up in the same region these peaks, so the apparent coupling patterns may appear distorted, due to the peak(s) for Ha.

3. If G = H, then it will appear in the aromatic region of the spectrum, and could complicate that region of the spectrum somewhat. If G = CH3 or OCH3, then it should appear as a single peak in the appropriate region of the spectrum. If G = CH2CH3, then you should see a triplet and a quartet at appropriate places in the spectrum.

4. If you started with a cyclopentanone or cyclohexanone, then the R's are some number of CH2 groups. You should see a peak for each type of CH2. These peaks often appear as lumps, because coupling in cyclic compounds is more complex, so the N + 1 rule may not apply. The peaks for the G groups may overlap the peaks for the CH2's, so be sure to use the integration values to check the number of H's in each set of peaks, especially if the peak looks distorted or unusual.

5. If your ketone was 4-methylcyclohexanone, then the methyl group will be split by the adjacent CH into a doublet. The CH and the CH2’s are coupled to each other, and may form some complex patterns, due to the CH2’s not being free to rotate.

3

The following table gives the reported melting points of the Aldol condensation products derived from each combination of aldehyde and ketone.

Aldehydes

Ketones

C

O

H

Benzaldehyde

CO H

CH3

p-tolualdehyde(4-methyl

benzaldehyde)

CO H

CH2CH3

4-ethylbenzaldehyde

CO H

OCH3

p-anisaldehyde(4-methoxy

benzaldehyde)

CH3

CCH3

O

Acetone

113 175 125-127 129-130

O

Cyclopentanone

189 235-236 147-148 212

O

Cyclohexanone

118 170 124-125 159

O

CH3

4-methylcyclohexanone

98-99 133-135 115-116 141-2

For example, the product derived from the reaction of benzaldehyde with cyclohexanone is reported to melt at 118C.

4

Report Format

A. Title Page

1. A descriptive title with between 10 & 20 words.2. Course and section number.3. Dates that the experiment was performed.4. Your name.

Tape your TLC plate to the bottom of the page, labeled clearly so I know what is what.

B. Body of the report.

1. A 2-3 sentence summary of your results (amount of product, melting point, identity of starting aldehyde and ketone).

2. Balanced chemical equation, using the actual structures you used.3. Important observations, and their interpretations, if possible. (colors of solutions

& solids, length of time until precipitate formed, etc.)4. Weight of crude product.5. Melting points of both crude and recrystallized products.6. TLC data, and calculations of Rf values for all spots.7. Calculations of theoretical and percent yields. Show calculations for the moles of

all reactants. Identify the limiting reagent.

C. Questions

1. Explain in detail how you used all of the data you obtained to determine the structure of your product. How did you distinguish between close choices? Did all of your data point to the same structure? If not, how did you decide which structure was correct? Include your NMR spectrum with your report. Interpret your NMR spectrum by drawing the structure of your product on the spectrum, and showing which H's in your structure give rise to which peaks in your spectrum. Explain the coupling patterns and any unexpected peaks.

2. What do your melting points tell you about the purity of your products? What do your TLC data tell you about the purity of your products? How accurate do you think these data are? Explain.

3. What impurities are removed by the ethanol and acetic acid in ethanol washes? Explain your reasoning.

5