Introduction Aldol Type Condensations

Aldol Type Condensations on Supported Reagents

Written by
David A. Nelson

General Procedure for Aldol-Type Condensations Using SPE Tubes and Ion-Exchange Resins

  1. Fit a 8 mL SPE reservoir with a closed stopcock and support it in an appropriate fashion. If the reservoir does not have a frit in the bottom, insert one. Make sure that the frit is pressed down evenly.
  2. Add about 2 mL (1/4 full) of a strongly basic anion exchange resin in the hydroxide form to the reservoir. A convenient way to do this is to make a slurry of the resin in the solvent being used and use a poly transfer pipet that has had the tip cut back so that it will suck up and hold the resin slurry.
  3. Allow the resin to settle. Open the stopcock and allow the solvent to drain from the tube. If a vacuum system is available, the solvent can be sucked out and the stopcock closed.
  4. Mix the reagents to be used in a test tube with 0.5 mL of solvent (or more if necessary for solution of the starting materials) and transfer the mixture carefully to the top of the resin bed in the reservoir with a poly transfer pipet. Wash the test tube with another 0.5 mL of solvent and add this to the reservoir.
  5. If necessary, add solvent until it is about 1-2 mm above the top of the resin bed. The idea is to have the reaction solution in contact with the entire resin bed. Agitate gently to mix the reagent solution. One way of doing this is to insert a 1 mL calibrated poly transfer pipet to the bottom of the resin bed and squeeze the bulb slowly. The expelled air bubbles will mix the reactants. If the resulting solution is much above the resin bed, cap the tube and shake it occasionally.
  6. Allow the solution to stand for 30 minutes, or as directed by your instructor.
  7. After this time if it appears that product has crystallized in the reservoir tube add enough solvent to dissolve the product. To aid in solution the top of the reservoir may be capped and the tube shaken.
  8. Open the stopcock and allow the contents to drain into a flask, or suck the contents through with a vacuum device. Wash the resin with one bed-volume of solvent.
  9. Analyze the solution to determine the percent conversion of reactant to product, and/or isolate and purify the product as directed by your instructor.

     

Specific Procedures:

  1. For Chalcone, use 0.5 mmol each of benzaldehyde and acetophenone.
  2. For 4-methoxychalcone, use 0.25mmol each of 4-methoxybenzaldehyde and acetophenone. Larger amounts tend to crystallize in the reservoir. Use 50/50 ethanol/acetonitrile for a solvent.
  3. For Dibenzalacetone, use 0.25 mmol of acetone and 0.50 mmol of benzaldehyde.
  4. For Monobenzalacetone, use 0.25 mmol of benzaldehyde and 2.0 mmole of acetone.
  5. Amounts for other chalcones have not been optimized. It is recommended to start with 0.1 mmol each of the substituted benzaldehyde and substituted acetophenone.
  6. The liquids are most conveniently measured by volume using a microliter syringe.

Safety Considerations: Have available MSDS for all reactants and solvents used. Assign reading to your students as required by your institutional safety policies. In general, ethanol is listed as a flammable liquid and an irritant. Most of the suggested reactants are listed as irritants. Benzaldehyde has a cancer suspect rating on the MSDS from Aldrich, and it is listed as such on the label. Carcinogenicity is based on one rat test; the mouse test was negative. There is no evidence of human toxicity. The FDA allows the use of benzaldehyde as a food additive. Artificial almond flavor is 65% benzaldehyde and 35% alcohol. Other suppliers usually list it as a toxic irritant. If you need to avoid the potential carcinogenicity, use a substituted benzaldehyde. If appropriate, the use of benzaldehyde can serve as an example of how to handle a carcinogenic substance in the lab. As a minimum this entails goggles, gloves, and lab coats, and the use of a "Designated Area". The hydroxide ion exchange resins are listed as eye irritants, but are much less hazardous than the concentrated NaOH solutions used in solution methods. If you convert the chloride form of the resin, aqueous NaOH will be required. It is recommended that the conversion be done by lab assistants or the faculty in charge. Ethanol is a toxic, flammable liquid.

Waste Disposal Considerations: The used ion exchange resins can be recycled and should not be considered as waste. As part of the procedure students can be instructed to empty the resins into a specific container containing 1N NaOH. This will regenerate any ion exchange sites that may have been exchanged. The most probable cause of the exchange is the formation of the benzoate anion resulting from aldehyde oxidation. Some reactants seem to discolor the resins but that should not affect their behavior as catalysts. After a sufficient amount of catalyst is recovered it should be filtered on a sintered glass funnel, washed to neutrality, and used again.

The SPE reservoirs, frits, and stopcocks can be used repeatedly. Leave the frit in the reservoirs and wash them with a small amount of ethanol. The only waste from this procedure should be the ethanol or other solvents used for recrystallizations.

General Procedure for "Dry Media" Aldol Condensations using KOH/Alumina

  1. Prepare the KOH/Alumina by dissolving 1.0 g of potassium hydroxide in 100 mL of methanol, and adding 10.0 g of neutral Activity Grade I chromatographic alumina. Scale up as necessary allowing 1.0 g of supported reagent for each experiment. Evaporate the slurry using a rotary evaporator at about 90 degrees for 1 hr with water aspirator vacuum. A free flowing powder containing about 5% residual methanol should result.
  2. Fit a 8 mL SPE reservoir tube with a frit and stopcock and add 1 g of the supported reagent.
  3. Dissolve 0.25 mmol of each reactant in 0.1 mL of MTBE (or other non-polar solvent) and add the solution onto the KOH/alumina reagent in the SPE tube. Liquid reactants can be added directly with no solvent.
  4. Cap or stopper the SPE tube and rotate it until the reactants appear evenly distributed on the alumina. This may take several minutes. No lumps should be evident. If a color begins to form, this should appear evenly distributed over the alumina.
  5. Rotate the tube periodically during the course of the reaction.
  6. After the reaction period is complete, wash the product from the support by adding at least 2 mL of MTBE or other non-polar solvent to the tube, placing a test-tube under the stopcock, and opening the stopcock. This is equivalent to eluting a small-scale chromatography column. It is convenient to use a vacuum device for this step. If the product is colored, the elution can be followed by observing the loss of color of the support. Colored by-products are usually formed in these condensations which are more strongly held than the desired product. Methanol or ethanol will wash the KOH off the support.
  7. The purity of the eluted product can be followed using TLC or HPLC if available.
  8. If product isolation is desired, evaporate the elution solvent and recrystrallize the product from the appropriate solvent.

Reaction Times: Yields of dry-media reactions vary considerably. Yields of 60-80% are usually obtained in 2-3 hrs. Reaction can remain for longer periods of time, up to one week, but often side products increase. To improve yields allow the reactants to sit as long as possible during the lab period and then elute the product; work it up next period if that is desired. "Overnight" or 24 hr seems to be an optimum time for complete reaction to take place.

Notes:

 

It is important that the aldehydes used be free of any corresponding acids. We routinely shake benzaldehyde or liquid substituted benzaldehydes with bicarbonate solution before use. Solid substituted benzaldehydes should be recrystallized or otherwise purified to remove any suspected acid impurities.

The resin used for Aldol Condensations is Amberlite IRA-400 (OH) which may be purchased from Aldrich. Wash the resin several times in the solvent to be used before running the reaction. SPE tubes with 8 ml reservoirs, frits and stopcocks may be purchased from Alltech.


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© February 1996.


DISCLAIMER:

These experiments are designed to be used in college and university level chemistry laboratory courses, and assume the availability of routine supplies, equipment, and instrumentation usually associated with organic chemistry laboratory courses, as well as an appropriate modern level of supervision, safety training, personal protective equipment, and other safety facilities. Any users of these procedures assume all responsibility for the safe handling of hazardous chemicals and procedures. In any event the authors, webmasters, The University of Wyoming , Rochester Institute of Technology, or Dartmouth College shall not be liable for incidental or consequential damages in connection with, or arising out of, the furnishing, performance, or use of these procedures.