Organic Chemistry Laboratory I
Acid Catalyzed Isomerization of Carvone to Carvacrol
Experimental Procedure

Introduction
Students will work in pairs to prepare carvacrol from carvone.  The procedure involves a simple reflux and work-up of the reaction mixture by extraction.  The reaction is monitored by TLC and a percent yield of the product is determined.  Spectra of the carvacrol product will be generated (IR) or provided (1H NMR), analyzed for consistency with the structure of carvacrol and compared with spectra data of the starting carvone. 



Figure 1:  Synthesis of Carvacrol from Carvone
Procedure
Synthesis of Carvacrol
Clamp a 50ml round-bottomed flask to a ring stand and place the reaction flask into a snug-fitting, 50ml  heating mantle.  Position the reaction set-up on the side of the hood with the faucet labeled "distillation set-up".  Set the heating mantle on a stirrer/hotplate.  Using a funnel, dispense 2 ml of carvone and 20ml of 6M H2SO4  into a the  flask using a funnel (Figure 2). CAUTION!!  6M H2SO4 is very strong acid.  Wear gloves and rinse them under water after handling acid. Add a magnetic stir bar and gently begin to stir the reaction mixture by turning on the magnetic stirrer. Connect the heating mantle to a Variac.  Be sure to twist the plug tightly to ensure appropriate connectivity.  Insert a condenser tube into the reaction flask and attach the water hoses (in at the bottom, out at the top) (Figure 3). Insert a drying tube into the top of the reflux apparatus.  Turn on the water. 

Plug the Variac into the wall outlet and set the dial to between 50 and 60V. Turn on the Variac and heat the reaction mixture to reflux (i.e, until the contents is boiling and the vapors condense and drip back into the flask) for 35 minutes. 


Figure 2:  Dispensing reagents into rb flask

         
      Figure 3:  Reflux apparatus
    
While the reaction mixture is refluxing, obtain two, clean and dry 50ml Erlenmeyer flasks or beakers.  Label one as "organic layer" and the other as "aqueous layer".  Set the flasks aside. 

Reaction Work Up
After 35 minutes, turn off the Variac and allow the reaction mixture to cool completely to room temperature.  Remove the condenser tube and insert a glass funnel into the neck of the flask.  Add 10ml of petroleum ether to the reaction flask and swirl the contents.  Transfer the mixture to a 100ml Erlenmeyer flask and label the flask as "crude reaction mixture".   Set up a 125ml separatory funnel on a ring stand as shown in Figure 4.  Close the stopcock on the separatory funnel and dispense the crude reaction mixture into the separatory funnel using a glass funnel.  Allow the mixture to settle.  Two layers should be observed.   Remove the glass funnel and place the stopper in the top of the separatory funnel. Shake the funnel as illustrated in Figure 5.  Return the separatory funnel to the ring stand an allow the layers to separate again.  Separate the two layers and dispense each layer into the two clean 50ml beakers or Erlenmeyer flasks prepared earlier, placing the organic layer into the flask labeled "organic layer" and the aqueous layer into the flask labeled "aqueous layer".  (To determine which is the organic layer add a few milliliters of petroleum ether to each layer.  If the few milliliters is miscible, that's the organic layer; if it separates out, its the water layer.)  Return the aqueous layer to the separatory funnel.  		     
 

 Figure 4:  Separatory funnel




Figure 5:  Shaking the separatory funnel
    
Add an additional 10ml of petroleum ether to the separatory funnel, shake again and allow the layers to settle for a second time.  Dispense the organic layer into the beaker containing the first organic layer.  Save the water layer and set it aside. Return the combined organic layers to the separatory funnel and add 20ml of 5% NaHCO3.  Shake the separatory funnel as in the previous steps and allow the layers to separate.  Dipsense each layer into labeled, clean, dry 50ml beakers or Erlenmeyer flasks.  Label one as "organic layer 2" and the other as "water layer 2".  Add 20-50mg of MgSO4 or Na2SO4 drying agent to the organic layer and swirl until the drying agent moves freely in the flask.  Filter the mixture to remove the drying agent and collect the filtrate into a clean,  dry 50ml Erlenmeyer flask.  The filtrate will contain the synthesized product.

TLC Analysis of the Reaction
Run a TLC of the product in the petroleum ether solution against the starting material.   Use silica gel plates as stationary phase and determine an appropriate solvent system for developing the TLC plate, starting with 50:50 hexane: ethyl acetate.  Adjust the polarity of the developing solvent to acheive Rf values in the range of 0.2-0.8.  Report the specific TLC conditions used to achieve these Rf ranges.

Isolating the Pure Product and Determining Percent Yield
Evaporate the solvent from the reaction mixture using a water bath. Clamp the flask containing the carvacrol product in petroleum ether solution to a ring stand.  Immerse the flask partially into a water bath, set on a hot plate/stirrer.  Place a magnetic stir bar into the flask and begin stirring the solution.  Turn on the hot plate to heat the water bath.  Allow all of the peteroleum ether to evaporate from the product.  Place the product under high vacuum for 15-20 minutes to remove any residual solvent. Allow the flask to cool to room temperature.  The product tends to become crystalline at ~200C.  Tranfer the product to a pre-weighed vial.  Re-weigh the vial containing the product and calculate the mass of product and the percent yield. 



IR and 1H NMR Spectroscopy
Analyze the product by IR spectroscopy using salt plates (If the product is crytalline, warming it slightly with a heat gun will cause it to melt and distribute on the salt plate.)  Run an IR spectrum of the starting material for comparison.  Report the major peaks in the spectrum of carvacrol and identify the bonds in carvacrol that give rise to these peaks.  Report the major peaks for carvone and identify the bonds in carvone that give rise to these peaks.  Record this data  in tabular form in your notebook.  Determine if the spectrum is consistent with the structure of carvacrol.
Download the 1H NMR spectrum for carvacrol and carvone from the website.  For carvacrol, list the major peaks, chemical shifts and the specific protons in the structure of carvacrol that give rise to each peak in the spectrum.  Do the same for the carvone spectrum.  Record this data in tabular form in your notebook.   Label the vial containing the remainder of your product and hand in the product. 
Waste Disposal
Dispose of excess petroleum ether in the non-halogenated organic waste.  Dispose of sulfuric acid in the aqueous acid waste.
Wash all glassware thoroughly with both soap and wwater and acetone.  Be especially carefully to clean all glassware that comes in contact with the sulfuric acid.