In the Laboratory
Thermodynamically and Kinetically Controlled Enolates: 1 A Project for a Problem-Oriented Laboratory Course Augustine Silveira, Jr.* and Michael A. Knopp** Chemistry Department, State University of New York at Oswego, Oswego, NY 13126 Jhong Kim* Chemistry Department, University of California, Irvine, Irvine, CA 92717 It is believed that the importance of undergraduate class research project laboratories as teaching tools will increase. Here we report an open-ended project that allows a great deal of flexibility. This project, undertaken by SUNY Oswego and University of California, Irvine, students who had previous involvement in project-oriented laboratories (1–7), can be readily adapted to the microscale organic laboratory (8, 9). The overall synthetic pathway is presented below. O-K+
O
OB-Et3K+ 1.CH3I
B(C2H5)3
KH
O
THF, r.t.
1
(1)
2. NaOH, H2O2
2
TB
T
(eq 1) or potassium bis(trimethylsilyl) amide (eq 2), respectively. The enolates are then treated with triethylborane to afford the corresponding potassium enoxytriethylborates KB and TB. We have shown (12) that when the reactions are carried out with various ketones without triethylborane, both the selectivity with respect to regiochemistry and the yields are considerably lower. Finally, if methyl iodide is added, followed by basic hydrogen peroxide, 2,2-dimethylcyclohexanone (2) is by far the major product when the hydride serves as the base, whereas a mixture of cis- and trans-2,6-dimethylcyclohexanone (3 and 4) predominates when the amide is used instead. The following observations are particularly noteworthy: 1. In the reaction of the kinetic enoxytrialkylborate derived from 2-methylcyclohexanone, the 2,6-:2,2-isomer ratio for different classes ranged from 95:5 to 98:2. As the reaction of 2-methylcyclohexanone with potassium bis(trimethylsilyl) amide is known to give a 95:5 mixture of potassium 6- and 2-methylcyclohexenolates (10, 13), the overall alkylation sequence must be regioselective. 2. One easily obtains the kinetically controlled product in good yields despite the relatively high temperatures (0 to {5 °C ) used. Usually temperatures on the order of {78 oC are required to obtain high yields of the kinetic product. 3. In all cases (both kinetic and thermodynamic), the less stable trans isomer (14) of 2,6-dimethylcyclohexanone was obtained. This result supports the idea that alkylation occurs via axial attack and that, owing to steric considerations, the conformer of the enoxytrialkylborate having the methyl group in a quasiaxial orientation is slightly preferred energetically, as is shown in eq 3.
Major Thermodynamically Controlled Product (10)
O
O-K+
O
OB-Et3K+ 3
KN[SiMe3]2 THF, 0 °C
2. NaOH, H2O2 3. heat
1
(2)
1.CH3I
B(C2H5)3
K
O
KB
4 Major Kinetically Controlled Products (10)
From a pedagogical point of view, this class laboratory project is exceedingly useful as it stands, providing for student involvement and discussion of the following first-course concepts: acid–base strengths, equilibrium, stereochemistry, enolate anion chemistry, reaction at carbon versus oxygen, ion pairs, solvent cage effects, axial alkylation, and kinetic and thermodynamically controlled regioselective products. The project involves regioselective alkylations of 2-methylcyclohexanone via thermodynamically and kinetically controlled enolates. Despite numerous developments (11) in the area of chemistry of enolates, it remains difficult, in many cases, to control regiochemistry, stereochemistry, and the number of carbon–carbon bonds formed in the reaction of enolates with carbon electrophiles. In this project, potassium enoxy trialkylborates, readily obtainable by treating potassium enolates with trialkylboranes, undergo remarkably selective reactions with methyl iodide. The synthesis involves first converting the ketone (1) to the potassium enolate K or T, using potassium hydride
*Corresponding authors. **Present address: University of Maine, Presque Isle, ME 04769.
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CH3
CH3 H
CH3I
O
H
CH3 CH3
axial attack
B-Et3K+
O
CH3
O
(3) CH3 H
O
H B-Et3K+
CH3I
O
axial attack
CH3
CH3
This result is analogous to enolate anions of 2-methylcyclohexanone derivatives, where the solvent shell about the metal cation destabilizes an adjacent equatorial substituent (15, 16). This leads to a relative stabilization of the 6-methyl substituent in an axial position and the consequent isolation of a substantial percentage of the trans isomer, following kinetically controlled protonation (15). Similar results have been reported in an NMR study of protonated methylcyclohexanones (17).
Journal of Chemical Education • Vol. 75 No. 1 January 1998 • JChemEd.chem.wisc.edu
In the Laboratory Interestingly, an equilibrium study by Kim (Kim, J.; unpublished results, University of California, Irvine, 1994) showed that in the kinetically controlled run, an initial cis:trans ratio of 33%:67% was obtained before H2O 2/NaOH treatment, and this reverted to 52%:48% only after 12 days at room temperature. Thus equilibration in this case is a very slow process, and the more stable cis isomer predominates only after 12 days at room temperature. One can readily adapt this project to study the reaction of other electrophiles, in addition to methyl iodide, with 2-methylcyclohexanone. Experimental Procedure CAUTION : Care should be exercised in handling methyl iodide, pentane, tetrahydrofuran (THF), sodium hydroxide, 2-methylcyclohexanone, hydrogen peroxide, potassium hydride, potassium bis(trimethylsilyl) amide, and triethylborane. Chronic exposure to methyl iodide has been reported to cause cancer in laboratory animals. Hydrogen peroxide and sodium hydroxide cause burns. Potassium bis(trimethylsilyl) amide, triethylborane, and potassium hydride emit toxic fumes under fire conditions. Potassium hydride also catches fire when exposed to air. 2-Methylcyclohexanone, pentane, and tetrahydrofuran are flammable and should be treated accordingly. Yields of products reported are the composite yields of several student sections at SUNY Oswego and the University of California, Irvine. The scale of reaction was readily reduced by some individual students without seriously decreasing yields (GC).
Regiospecific Alkylation of 2-Methylcyclohexanone with Methyl Iodide (Thermodynamically Controlled Enolate Intermediate) Using nitrogen, flush a 15-mL two-neck conical flask equipped with a septum inlet, a magnetic stirring bar, and an outlet connected to an oil bubbler. Place 210 mg of potassium hydride (22% w/w in mineral oil contains 46 mg of KH, 1.1 mmol) in the flask. Add 1 mL of dry pentane and stir the mixture briefly. Allow the suspension to settle with occasional tapping. Remove the pentane–oil mixture with the help of a syringe without disturbing the settled KH. Repeat this step with another milliliter of pentane. Then add 1 mL of dry THF to make a slurry of KH. With the aid of a syringe, add 112 mg of 2-methylcyclohexanone (0.121 mL, 1.0 mmol) in 1 mL of THF drop by drop to the solution over a 15-min period while stirring efficiently at room temperature. Add triethylborane (1.25 mL of 1 M solution, 1.25 mmol) slowly (it should take approximately 20 min) with the aid of syringe that has been purged with dry nitrogen; then add 214 mg of methyl iodide (0.094 mL, 1.5 mmol) dropwise over a period of 20 min. Allow to react for 1 h at room temperature. After adding 0.6 mL of 3 M sodium hydroxide (large excess), cool the mixture to 0 °C and add dropwise 30% hydrogen peroxide (0.6 mL, large excess). Heat the reaction mixture to 50 °C and stir it for an hour at this temperature. Saturate the aqueous phase with potassium carbonate. Separate the organic layer and analyze the product composition by gas chromatography. Calculate the relative percentage composition of all isomeric products. Regiospecific Alkylation of 2-Methylcyclohexanone with Methyl Iodide (Kinetically Controlled Enolate Intermediate) Using nitrogen, flush a 15-mL two-neck conical flask with a septum inlet, a magnetic stirring bar, and an outlet connected to an oil bubbler. Place 220 mg of potassium bis(trimethylsilyl) amide (1.1 mmol) in the flask. Add 1 mL
of dry THF to dissolve the amide. Place the flask in an icewater bath to maintain the reaction temperature (0 to 5 °C). Add slowly 112 mg of 2-methylcyclohexanone (0.121 mL, 1.0 mmol) in 1 mL of THF to the solution over 15 min with the aid of syringe while stirring efficiently. Maintain the reaction temperature 0 to {5 °C. Add triethylborane (1.25 mL of 1 M solution, 1.25 mmol) over 20 min with the aid of a hypodermic syringe that has been purged with dry nitrogen; follow this by adding 214 mg of methyl iodide (0.094 mL, 1.5 mmol) over 20 min. Allow to react for 1 h and then remove the icewater bath. After adding 0.6 mL of 3 M sodium hydroxide, cool the mixture to 0 °C and add 0.6 mL of 30% hydrogen peroxide over 5 min. Heat the reaction mixture to 50 °C and stir for an hour at this temperature. Saturate the aqueous phase with potassium carbonate. Separate the organic layer and analyze the product composition by gas chromatography. Calculate the relative percentage composition of all isomeric products.
Gas Chromatographic Analysis All products were readily separated using the following equipment and conditions: gas chromatograph, HewlettPackard 5890, Series II; column, 25 m fused silica capillary column #28153, Alltech Associates; column temperature, 70 °C; injection temperature, 150 °C; detector temperature, 160 °C; detector, FID; carrier gas, He; flow rate, 30 mL/min. A Gow Mac Series 350 GC (column, 25% SE30 on chromosorb W NAW 80-100, 20', 1/8" stainless steel) and a Varian 3400 GC (column, 3% SP 2100 on Supelcoport 100/120, 8', 1/8" stainless steel) were also successfully used, but better separations were obtained with the capillary column. Authentic samples of 2-methylcyclohexanone and various dimethylcyclohexanones can be obtained from Aldrich Chemical Co. Typical gas retention times with THF solvent with the above gas chromatographic conditions are THF, 2.2 min; 2-methylcyclohexanone, 5.4 min; 2,2-dimethylcyclohexanone, 6.7 min; cis-2,6-dimethylcyclohexanone, 7.2 min; trans-2,6-dimethylcyclohexanone 7.5 min. In the thermodynamically controlled run, isolated yields of the major 2,2-dimethylcyclohexanone product ranged from 75 to 95%, with typical trans:cis ratios of the minor 2,6- product in the range of 60–65% trans to 35–40% cis. In the kinetically controlled run, isolated class yields of the major trans/cis-2,6-dimethylcyclohexanone ranged from 80 to 90%, with typical trans/cis ratios of 55–60% trans to 40–45% cis after hydrogen peroxide and hydroxide treatment. As previously stated, over a period of time this ratio decreases until ultimately the cis isomer predominates. Acknowledgments A. Silveira, Jr., gratefully acknowledges the National Science Foundation (most recent NSF-ILI grant, No. 228-0388A) for its continued support of project-oriented laboratories. We thank the students in Chemistry 52LB at the University of California, Irvine, and Chemistry 334L students at the State University of New York (SUNY), College at Oswego. A. Silveira, Jr., thanks the Chemistry Department at the University of California, Irvine, where this project was initiated, for its support during his sabbatical leave and the Chemistry Department at SUNY, Oswego, for its support. Note 1. Presented in part at the 203rd National Meeting of the American Chemical Society, Chemical Education Division, San Francisco, CA, April 5–10, 1992.
JChemEd.chem.wisc.edu • Vol. 75 No. 1 January 1998 • Journal of Chemical Education
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In the Laboratory Literature Cited 1. Silveira, A., Jr.; Koehler, J. A.; Beadel, E. F., Jr.; Monroe, P. A. J. Chem. Educ. 1984, 61, 264–265. 2. Silveira, A., Jr. J. Chem. Educ. 1978, 55, 57. 3. Silveira, A., Jr.; Satra, S. K. J. Org. Chem. 1979, 44, 873. 4. Silveira, A., Jr.; Bretherick, H. D.; Negishi, E. J. Chem. Educ. 1979, 56, 560. 5. Silveira, A., Jr.; Orlando, S. C. J. Chem. Educ. 1988, 65, 630. 6. LeFevre, J. W. J. Chem. Educ. 1990, 67, A278. 7. Silveira, A., Jr.; Evans, J. M. J. Chem. Educ. 1995, 72, 374. 8. Mayo, D. W.; Pike, R. M.; Butcher, S. S. Microscale Organic Laboratory, Wiley: New York, 1986.
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9. Williamson, K. L. Macroscale and Microscale Organic Experiments, 2nd ed.; D. C. Heath: Boston, 1994. 10. Negishi, E.; Chatterjee, S. Tetrahedron Lett. 1983, 24, 1341. 11. For a review see Jackson, L. M.; Lange, B. C. Tetrahedron 1977, 33, 2737. 12. Negishi, E.; Idacavage, M. J.; DiPasquale, F.; Silveira, A., Jr. Tetrahedron Lett. 1979, 10, 845. 13. Brown, C. A. J. Org. Chem. 1974, 39, 3913. 14. Garner, C. M. J. Chem. Educ. 1993, 70, A310. 15. Malhotra, S. K.; Johnson, F. J. Am. Chem. Soc. 1965, 87, 5513. 16. Subrahmanyam, G.; Malhotra, S. K.; Ringold, H. J. J. Am. Chem. Soc. 1966, 88, 1332. 17. D’Silva, T. D.; Ringold, H. J. Tetrahedron Lett. 1967, 16, 1505.
Journal of Chemical Education • Vol. 75 No. 1 January 1998 • JChemEd.chem.wisc.edu
