In the Laboratory
Grignard Synthesis of Various Tertiary Alcohols T. Stephen Everett Department of Chemistry, Goucher College, Baltimore, MD 21204
We have developed a general Grignard procedure for the synthesis of a variety of aliphatic tertiary alcohols, which presents students with an added challenge of product identification. Many organic syntheses in the undergraduate teaching laboratory can be infused with an extra element of discovery simply by not revealing the specific starting materials. Substitutions of isomers or homologues for the prescribed organic reagents create multiple possibilities for unknowns. We have found inclusion of this type of puzzle helpful in combating the tendency of students to approach lab work in a mechanical or cookbook fashion (1, 2). Five articles on Grignard reactions have appeared in this Journal in the last 10 years (2–6). All organic laboratory manuals include at least one Grignard procedure. Phenylmagnesium bromide is the most commonly described Grignard reagent, used in the synthesis of triphenylmethanol (trityl alcohol) and benzoic acid (7–9). Our variation of the standard Grignard reaction incorporates anhydrous techniques, distillation, and infrared analysis to identify an unknown product. Experimental Procedure1 CAUTION : The organic reagents and products in this procedure are flammable. Diethyl ether is highly flammable. Flame drying of glassware should be completed by all students before diethyl ether is dispensed! RX + Mg → [RMgX] + R′R″C=O → [RR′R″COMgX] → RR′R″COH Criteria: RX = C2–C5 1° alkyl bromide (unbranched) R′R″C=O = C3–C 5 ketone RR′R″COH = C 6–C 9 3° alcohol {R, R′, R″ may be the same or different}
Each student receives one of four alkyl halides (bromoethane, 1-bromopropane, 1-bromobutane, or 1-bromopentane)2 and one of four ketones (acetone, butanone, 2pentanone, or 3-pentanone) in premeasured amounts as unknown starting materials. Students are also provided with a list of 14 possible products,3 shown in Table 1. All reagents and glassware used in this reaction must be dry! Magnesium turnings (0.88 g, 36 mmol) are weighed in a 100-mL round-bottom flask. A magnetic stirring bar is added and the flask is fitted with a Claisen adapter, separatory funnel, and condenser, then carefully flame dried with a Bunsen burner.4 An unknown alkyl halide (33 mmol) is transferred to the separatory funnel, then dissolved in 15 mL of anhydrous diethyl ether. Approximately 5 mL of this solution is added to the reaction flask (enough to cover the stir bar and magnesium) and the mixture is stirred vigorously. Initial signs of exothermic formation of the Grignard reagent (RMgX) include the development of cloudiness, warming, then bubbling of the ether solution. Once the reaction has commenced, the remaining alkyl halide/ether solution is added dropwise to maintain a continuous reflux of ether. Upon completion of this addition the reaction flask is mildly warmed to continue the reflux and stirred another 15 min.
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The reaction flask containing the Grignard reagent is cooled in an ice bath. An unknown ketone (30 mmol) dissolved in 5 mL of anhydrous ether is slowly added as the ice bath is raised or lowered to maintain a controlled reflux. After all the ketone has been added, the reaction is stirred at room temperature for 15 min. The reaction flask is cooled once more and 15 mL of 1 M sulfuric acid is added, slowly at first with stirring, to convert the alkoxymagnesium bromide salt (RR′R″COMgX) to the alcohol. The aqueous and organic layers are separated, the aqueous layer is extracted with an additional 10 mL of ether, and the combined ether solutions are washed with 10 mL of saturated NaHCO3, then dried over anhydrous MgSO4. The organic solution is filtered and the alcohol product is isolated by simple distillation.5 The observed boiling point, mass, refractive index, and infrared spectrum are recorded for each product. Discussion A successful Grignard reaction necessitates anhydrous laboratory technique and close control of exothermic processes. Product quality (purity) and quantity (yield) directly reflect student lab technique. Isolation of liquid products in this procedure requires selective collection of distillate (fraction cutting). The quantity-versus-quality trade-off becomes clear: greater yield can be obtained when distillate is collected over a wider temperature range, but sample purity is enhanced when distillate is collected at a higher, narrower temperature range. Unknown product identification utilizes physical (boiling points, refractive indices) and spectral (infrared O–H, C–H and fingerprint regions) data. Student IR spectra serve two functions: (i) for product identification by comparison with authentic spectra, and (ii) as a measure of sample purity6.
Table 1. Physical Data for C6–C9 Tertiary Alcohols bp (°C)
nD
2-Methyl-2-pentanol
122
1.410
3-Methyl-3-pentanol
123
1.419
3-Ethyl-3-pentanol
141
1.430
Compound Name
2-Methyl-2-hexanol
142
1.417
3-Methyl-3-hexanol
143
1.422
3-Ethyl-3-hexanol
160
1.430
4-Methyl-4-heptanol
161
1.425
2-Methyl-2-heptanol
162
1.424
3-Methyl-3-heptanol
163
1.428
2-Methyl-2-octanol
178
1.428
4-Ethyl-4-heptanol
182
1.433
4-Methyl-4-octanol
183
1.432
3-Ethyl-3-heptanol
184
1.437
3-Methyl-3-octanol
185
1.432
Journal of Chemical Education • Vol. 75 No. 1 January 1998 • JChemEd.chem.wisc.edu
In the Laboratory The 14 possible products are quickly reduced to five or fewer by boiling-point data alone. IR spectra of previously prepared samples are available for direct comparison. To identify the single correct structure, close inspection of the infrared spectra, especially the fingerprint region below 1500 cm{1 , is absolutely necessary. Once a product is identified, retrosynthetic considerations point to which alkyl halide and ketone were required as starting materials. Typical student yields are approximately 50%. Acknowledgment This experiment is presented in the second semester organic chemistry lab to both undergraduate and postbaccalaureate premedical students. I acknowledge the financial support of the Post-Baccalaureate Premedical Program of Goucher College under the direction of Barbara Berkowitz.
cluded in the table of possible products. Two additional compounds, 2-methyl-2-octanol and 4-ethyl-4-heptanol, cannot be synthesized by the criteria given, but are included in the table to complete the set of 6–9-carbon tertiary alcohols. Students are not told about these two “extras”, but are reminded of the limiting criteria and can eliminate these from consideration. 4. Alternatively, the glassware can be dried in a hot oven prior to use. We have found that additional efforts to maintain anhydrous conditions (drying tubes or inert atmosphere) were not necessary for satisfactory results. 5. Unreacted alkyl halide and ketone distill at lower temperatures than the alcohol product, altering the observed boiling points and refractive indices. Students are encouraged to have at least two tared receivers ready to collect distillation fractions discriminately. 6. Unreacted ketone is easily recognized by its carbonyl band at 1700 cm {1. The more intense this band appears, the less pure is the alcohol product.
Literature Cited
Notes 1. Supplemental teaching materials (lab preparation, student handouts, and infrared reference spectra) are available from the author upon written request. 2. Formation of the Grignard reagent from these four 1° aliphatic alkyl bromides proceeds smoothly. Most difficulties in the initiation of this reaction are due to wet glassware. 3. Fifteen tertiary alcohol products can be generated from combinations of these reagents. Only one, 3-methyl-3-hexanol, can be synthesized two ways by the criteria given. Three of the 15 do not meet the size criteria of 6–9 carbons and are not in-
1. 2. 3. 4. 5. 6. 7.
Todd, D.; Pickering, M. J. Chem. Educ. 1988, 65, 1100–1102. Silversmith, E. F. J. Chem. Educ. 1991, 68, 688. Eckert, T. S. J. Chem. Educ. 1987, 64, 179. Orchin, M. J. Chem. Educ. 1989, 66, 586–588. Kulp, S. S.; DiConcetto, J. A. J. Chem. Educ. 1990, 67, 271–273. Abhyankar, S. B.; Dust, J. M. J. Chem. Educ. 1992, 69, 76. Williamson, K. L. Macroscale and Microscale Organic Experiments; Heath: Lexington, MA, 1989; pp 354–368. 8. Pavia, D. L.; Lampman, G. M; Kriz, G. S.; Engel, R. G. Introduction to Organic Laboratory Techniques: A Microscale Approach; Saunders: Philadelphia, 1990; pp 241–251. 9. Ault, A. Techniques and Experiments for Organic Chemistry, 5th ed.; Waveland: Prospect Heights, IL, 1994; pp 410–414.
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