It is reported that the reaction of phenylmagnesium bromide with 2-methylcyclopentanone followed by acidic workup yields 2-methyl-1-phenylcyclopentanol. Acid-catalyzed dehydration using toluenesulfonic acid initially gives the less substituted alkene as the major product. Application of heat to the reaction mixture over a period of two hours reverses the distribution of products, to give the more substituted alkene as the major product in 91-96 % relative yield.

In the dehydration reaction of 2-methylcyclopentanol, the less thermodynamically stable product elutes first from a non-polar GC column and constitutes 55% of the two alkene products. However, as the reaction mixture is heated, its peak area decreases relative to that of the thermodynamically favored product which eventually becomes the major product. This can be predicted using computational methods. Calculations at the ab initio 6-31G* level of theory predicts the thermodynamically favored alkene to be 1.442 kcal/mol lower in energy.¹

General Procedures:

Grignard Reaction:
Preparation of (A) 2-Methyl- 1-ethylcyclohexanol and (B)2-Methyl-1-phenylcyclohexanol

1) Glassware must be dry. Use a heat gun to heat the assembled apparatus with the drying tube in place. Let cool before proceeding with step 2).

2) A magnetic stir bar, 19.6 mmol of fresh magnesium turnings, and 15 mL of anhydrous ether are placed in a 100-mL, single-necked roundbottom flask fitted with a Y adapter, reflux condenser and an addition funnel containing 19 mmol of a bromo-compound^* and 5.0 mL of anhydrous ether.

*  (A) Bromoethane  or  (B) Bromobenzene

A drying tube filled with calcium chloride is connected to the top of the reflux condenser. The bromo-compound:ether solution is then added dropwise at a rate of 1 drop per second with stirring. The appearance of a cloudy reaction mixture signals the initial reaction of magnesium with the bromide. The reaction is refluxed after all the bromo-compound:ether solution has been added. During this time, a solution of 19 mmol of 2-methylcyclohexanone in 10 mL of anhydrous ether is placed in the addition funnel. After refluxing for 30 min, the heat source is removed and the ketone solution is added dropwise at a rate of 1 drop per second to the Grignard. The heat given off allows the reaction to continue refluxing on its own . After all the ketone solution is added, the reaction mixture is the heated and reflux continued for an additional 15 min. The mixture is then cooled in a warm water bath additional cooling in an ice bath follows. An ether/ethanol solution is made by mixing 1.5 mL of ethanol and 10 mL of ether. While the reaction mixture is still in the ice bath, the ether/ethanol solution is placed in the addition funnel and added slowly (at a rate of about 1 drop per second) to the reaction mixture. Magnesium salts precipitate. Next, 20 mL of a 1 M sulfuric acid solution is placed in the addition funnel and added dropwise to the reaction mixture (still in the ice bath) to dissolve the magnesium salts. The stir bar is removed, and the contents of the flask are transferred to a separatory funnel. The lower aqueous layer is removed and extracted twice with 15-mL portions of ether. All three ether layers are combined and dried with anhydrous sodium sulfate. Gravity filtration of the drying agent yields a clear solution. The ether and ethanol are removed using simple distillation at low heat keeping a slow rate of distillation to give a slightly viscous yellow liquid. Heating should be kept to a minimum. DO NOT distill the alcohol. Determine the yield of crude alcohol and analyze by IR to verify the formation of an alcohol. Store the product in a sealed vial and save for the dehydration portion of the experiment.

Dehydration of 2-Methyl-3-phenyl-3-cyclopentanol:

A magnetic stir bar, approximately 4 mmol of the alcohol from the Grignard reaction, 20 mL of toluene, and 0.05 g of toluenesulfonic acid are placed in a 50-mL single-necked flask fitted with a reflux condenser. The flask is placed in a heating basket and the solution is refluxed with stirring. After 15 min, 2-4 drops of the reaction mixture are removed via a disposable pipette and added to a tube containing 0.5 mL of dichloromethane and 0.5 mL of l0% sodium bicarbonate. The reaction solution forms a brown layer at the top of the tube, giving three layers in total. The is stoppered and the contents are vigorously shaken. Upon settling, two layers form in the tube: an aqueous layer on top and a clear brown organic layer on the bottom. A GC syringe is used to take a 1-microliter sample from the lower dichloromethane layer. This sample is then analyzed by GC.^* Additional samples are taken from the reaction mixture in a similar manner every 15-20 min for a total of 2 hours. Record the sampling times in tabular form. The samples need not be analyzed immediately, since the sodium bicarbonate solution was used to neutralize the toluenesulfonic acid.

^{* The analysis in the literature was conducted with a research instrument, a programmable GC with a capillary column. Your analysis is purely experimental. The instructional GC that you have at your disposal may not separate the structural isomers.}

Pre-Lab Exercises:


• Each group member is to individually do either Reaction A or B. (Individual Products are to be collected.) Be sure that your group has two members doing A and two doing B.
• Write up an individual pre-lab report to include the normally required experimental information plus a sketch of the apparatus for the Grignard Reaction. Be sure to clearly indicate experimental amounts to be used for both the Grignard and dehydration reactions.
• Clearly label the alkene structures as the "Thermodynamic Product" (i.e. the most thermodynamically stable) and the "Kinetic Product" (i.e. the one that forms the fastest).
  

Additional Calculations and Plot:


• Use the formula: G = -RT In K.
• Solve for K using the thermodynamic data in the following table.The thermodynamic differences for the alkenes were calculated using MacSpartan's computational methods, MM2 and AM1 for molecular geometries and heats of formation. The energy difference E is taken relative to the more stable alkene. E is equal to G as an approximation. The temperature is the boiling point of toluene which is the solvent used in refluxing. (Consult a General Chemistry text for examples and a value for the constant R.)
• Calculate the % distribution of "Kinetic Product" and "Thermodynamic Product" for each reaction at equilibrium.




	E kcal/mol	% Kinetic Product	% Thermodynamic Product
methylphenyl cyclopentenes	-3.399380
ethylmethyl cyclohexenes	-3.070293
methylphenyl cyclohexenes	-2.883693




• The actual experimental values for the methylphenylcyclopentenes was 91% of the Thermodynamic product and 9% of the Kinetic product at equilibrium. Calculate G and compare the value to E above. What is the % error in the computational value?
• If your group was able to develop GC data for the other equilibrium distributions of the substituted cyclohexenes, provide the experimental data and the % error compared to the computational values above.
• Show an energy plot (Energy vs. Reaction Progress) illustrating the reaction mechanisms that produce each product for the dehydration of 1-phenyl-2-methylcyclopentanol using the actual experimental data at equilibrium in refluxing toluene. Clearly draw the transition states, reactive intermediates and electron movements.

Questions:

• See Assignment Web page.