The Aldol Condensation

Expt 9: The Aldol Condensation

INTRODUCTION Reactions that form carbon-carbon bonds are particularly important in organic chemistry as they allow the synthesis of more complex structures from simpler molecules. One of the more common types of these reactions are condensation reactions which occur between carbonyl-containing molecules, in which the enol or enolate of one carbonyl compound acts as the nucleophile, and a second carbonyl compound acts as an electrophile. If the carbonyl compounds are aldehydes or ketones, this process is known as the Aldol condensation. In a self-Aldol condensation, the same carbonyl compound condenses with itself, whereas in a mixed-Aldol condensation, the two carbonyl compounds are different. In the second case, careful choice of both components is required so that only a single product is formed. Usually one component is selected because it cannot form an enolate, and therefore can only act as the electrophile. These reactions may be catalyzed by either acid or base – we will be performing a base-catalyzed reaction using aqueous sodium hydroxide as the base.

The reactions we are doing in this lab are sometimes known as the Claisen-Schmidt condensation, which is a mixed-Aldol reaction between a ketone and an aldehyde. In our cases, the ketone is acetone, and the aldehyde component is benzaldehyde or p- methoxybenzaldehyde, often known as p-anisaldehyde. Of these compounds, only acetone can form an enolate anion, and it will preferentially react with the more reactive carbonyl group of the aldehyde, ensuring that we only get a single product. Acetone contains enolizable sites on both sides of the carbonyl group and thus a second condensation can occur with a second equivalent of benzaldehyde. The summary reactions are shown below:

O O O NaOH (aq) 2 + + 2 H2O H ethanol H3C CH3 dibenzalactone benzaldehyde O O O NaOH (aq) 2 + + 2 H2O H ethanol H3C CH3 H CO H CO OCH 3 3 dianisalacetone 3 p-anisaldehyde

1 EXPERIMENTAL OVERVIEW The key intermediates in the mechanism of these Aldol condensations are shown in the scheme below. Deprotonation of acetone with NaOH generates its enolate anion – this enolate anion is in equilibrium with free acetone as the pKa of acetone is 19.3 and NaOH is not a sufficiently strong enough base to ensure complete deprotonation. However, as benzaldehyde is a more reactive electrophile than acetone, the enolate will selectively act as a nucleophile towards it, forming a β-hydroxyketone intermediate. Both of these steps are reversible, but the β-hydroxyketone readily undergoes favorable dehydration under base-catalyzed conditions to form the α,β-unsaturated ketone product. The more stable trans-alkene is the only product of the dehydration. The reaction will stop at this stage, unless two equivalents of the aldehyde are present, in which case the process repeats itself. The methyl ketone can undergo enolization and reaction with a second equivalent of benzaldehyde forming another β-hydroxyketone, which also spontaneously dehydrates to give the final product, again as the trans isomer. O OH O O O O NaOH H CH3 H C CH H C CH 3 2 3 2 H3C CH2 H enolate anion β-hydroxyketone O - H O O OH 2 O O H NaOH CH2 CH3

- H2O enolate anion α,β-unsaturated ketone O (resonance not shown) Aldol condensation product

α,β-unsaturated ketone double Aldol condensation product

In the solvent system we are using, aqueous ethanol, the double-Aldol product crystallizes out of the reaction mixture and can be recovered by filtration. Washing with water removes traces of NaOH and the product is recrystallized from ethanol.

2 REAGENT/PRODUCT TABLE:

Reagents MW (g/mol) MP (ºC) BP (ºC) Density acetone 58.08 -95 56 0.79 benzaldehyde 106.13 -26 178 1.04 p-anisaldehyde 136.15 -1 248 1.12 10% NaOH(aq) 40.01 (of solute) 1.11 ethanol (95%) -114 78 0.789

Products MW (g/mol) MP (ºC) BP (ºC) Density dibenzalacetone 234.3 110-111 dianisalacetone 294.36 130-131

FOR YOUR SAFETY: 1.Wear gloves when dispensing reagents. If NaOH is spilled on the skin, immediately rinse off with plenty of flowing water. 2. Ethanol is highly flammable.

Your instructor will assign the aldehyde component you should use in Step 2. Otherwise, the procedures are the same.

EXPERIMENTAL PROCEDURE: 1. Obtain a clean, dry 5 mL conical reaction vial with a spin vane and add 2 mL of 10% sodium hydroxide solution. Place it in the aluminum block on your stirrer/hotplate and commence stirring. Do not heat!

2. Record the mass of a clean, dry small sample vial. Then add the following: Benzaldehyde only: In the hood, dispense 0.20 mL of benzaldehyde into this vial. Reweigh the vial and determine the mass of benzaldehyde you are using. p-Anisaldehyde only: In the hood, dispense 0.24 mL of p-anisaldehyde into this vial. Reweigh the vial and determine the mass of p-anisaldehyde you are using. (Using the density, calculate to determine if your mass is close to what is expected for your measured volume.)

3. Using a Pasteur pipette, add the aldehyde to the stirring sodium hydroxide solution in the conical vial on your hotplate. Obtain a clean, dry large sample vial from your locker and fill the vial one-third full with 95% ethanol (JUST ETHANOL, NOT THE ETHANOL AND ACETONE MIXTURE). Use a small volume (few drops only) of ethanol to wash out the sample vial and add the washings to the conical vial using

3 the same pipette. [Note whether the aldehyde does or does not dissolve into the solution.]

4. In the hood, transfer 1.6 mL of the acetone/ethanol solution to another clean, dry sample vial. [Note: This solution contains 58 mg of acetone in each 1.6 mL of acetone/ethanol solution].

5. At your bench, transfer the acetone/ethanol solution to your conical vial containing the other reactants with a Pasteur pipette. Then place a cap loosely on the conical vial.

6. Stir the reaction for 30 minutes at room temperature (No Heating!) and make a note of any observations.

7. After 30 minutes, you should have observed solid or crystal formation. Set up your Hirsch funnel for vacuum filtration.

8. Add 1-2 mL DI (deionized) water to the conical vial until it is full, and break up any solids in the vial with a microspatula to make them easier to transfer. Pour the contents of the vial onto the Hirsch funnel and filter the solid.

9. To ensure complete transfer of all the solids into the Hirsch funnel, wash out the conical vial twice, using two 3 mL portions of DI water, transferring all washings into the Hirsch funnel each time. Each time, turn off the vacuum before each transfer to ensure that the water contacts the solids in the funnel sufficiently to properly wash the solids.

10. Pull a vacuum on the crystals for ~5-10 minutes to air dry.

11. Once the crude product crystals are dry, transfer them to a small (25 mL) pre- weighed Erlenmeyer flask. Reweigh to obtain the mass of the crude product.

12. Place the sample vial containing your ethanol supply on the hotplate set to a low setting (2-3) and heat until the ethanol is just boiling.

13. Using a Pasteur pipette, add 1 mL of hot ethanol to your product in the Erlenmeyer flask, swirl to dissolve and place on the hotplate to keep warm.

14. Continue adding hot ethanol in small portions with swirling until all the crude product dissolves (you should only need 2-3 mL so do not add too much at one time!).

4 15. Remove the flask from the hot plate and allow to cool to room temperature slowly on the benchtop, and then further cool the solution in an ice bath. Crystals should form – if not, scratch the bottom of the flask with a glass stirring rod to induce crystallization. Place ethanol from hot bath in ice bath to cool also.

16. Clean your Hirsch funnel and re-assemble the filtration apparatus. Once crystallization appears complete, isolate the crystals by vacuum filtration, and wash with one 1 mL portion of ice-cold ethanol. Pull air through for about 5 minutes to further dry the crystals.

17. Leave the crystals to dry on your filter funnel standing in a small beaker in your locker until next week, when you will obtain a weight (weigh small sample vial and cap, transfer product, reweigh small sample vial and cap) determine your product’s melting point and obtain an IR spectrum on your product. After completing the MP and IR, submit your product (properly labeled).

WASTE DISPOSAL

1. The filtrates should be placed in the waste container labeled “aqueous basic waste.” [Condensation Waste container] 2. Carefully wash all the apparatus used in this experiment in the sink and return the glassware and equipment to your lab station.

CALCULATIONS

1. Calculate the number of moles of aldehyde used (make sure to use the mass of aldehyde and not the volume) 2. Calculate the number of moles of acetone used. 3. Determine which component is the limiting reagent (remember the mole ratio!) 4. Calculate the theoretical yield of your double Aldol condensation product. 5. Calculate the percent yield of your double Aldol condensation product. 6. Calculate the percent recovery for your Aldol product recrystallization process.

5 BENZALDEHYDE, 98+% 98

52 %Transmittance

12 10

4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 1800 1600 1400 1200 1000 800 600 Wavenumbers (cm-1)

Date: Unknown BENZALDEHYDE, 98+%

Scans: 1 00700044

Resolution: Unknown P-ANISALDEHYDE, 98% 98

52 %Transmittance

12 10

4000 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 1800 1600 1400 1200 1000 800 600 Wavenumbers (cm-1)

Date: Unknown P-ANISALDEHYDE, 98%

Scans: 1 41501146

Resolution: Unknown