In the Laboratory
Side Reactions in a Grignard Synthesis Hilton M. Weiss Department of Chemistry, Bard College, Annandale-on-Hudson, NY 12504
The availability of modern analytical techniques provides an interesting opportunity for undergraduates in our organic laboratory to analyze their products and often find unexpected side products in significant quantities. Identification of these products has often stimulated some creative thinking about the mechanism and synthetic potential of these side reactions. Some of our students have designed and performed further experiments to test their ideas. We previously described one such experiment showing the presence of 30% 3-hexanol in the hydration of 1-hexene (1). More recently, we have turned up some surprises in the Grignard synthesis of secondary alcohols. We have students make butylmagnesium bromide and add propionaldehyde or acetone to produce secondary or tertiary alcohols, respectively. We use the same procedure for both of these reactions but point out that the weak acid, ammonium chloride, is used to acidify the tertiary alcohol because it is fairly reactive toward hydrochloric acid. The interesting twist occurs when students analyze the distilled 3-heptanol coming from propionaldehyde. An IR spectrum shows a strong carbonyl peak. Gas chromatography shows an initial small peak (≈5%) followed by a larger peak (≈20%), followed by the major peak of 3-heptanol. GC-MS identifies the first peak as octane and the second peak as 3-heptanone. It also shows a small peak appearing much later with a mass spectrum consistent with 5-ethyl-5-nonanol. The presence of this product is significant because it derives from the reaction of the Grignard reagent with 3-heptanone which must have been formed during the addition of the Grignard reagent. Realizing that the magnesium heptoxide is oxidized to 3-heptanone, students are encouraged to find the requisite reagent that is being reduced. Propionaldehyde is the only reasonable candidate. Experimental support for this assumption may be obtained by using a large excess of propionaldehyde in the reaction. In our hands, a fourfold excess produced 3-heptanone as the major product. This side reaction is synthetically useful and is a variation of the Oppenauer oxidation. Students are encouraged to read about this and to think of reasons why it happens (2).
Et Bu
Br
Br
Mg
Mg
O
O
O
C
C
C
H
Et
Et
H
Bu
O C H
Et H
The equilibrium between the heptoxide plus propionaldehyde and the heptanone plus n-propoxide is driven to the right by the excess and relative instability of the aldehyde. The reducing ability of the magnesium heptoxide is also a good model for discussing the zinc ion catalysis in the NAD+ oxidation of alcohols. Understanding this reaction can also lead to correcting the problem. We have found that the addition of isopropyl 76
alcohol to the reaction mixture prior to acidification causes precipitation of some mixed magnesium salts. Distillation of ether, propionaldehyde, and acetone from this mixture shifts the equilibrium toward the formation of 3-heptanol. Working up the remaining mixture gave us 3-heptanol with only a few percent of the ketone impurity. When run in this direction, this reaction is usually referred to as a Meerwein–Pondorff– Verley reduction. The real value of this experiment lies in the deductive process involved and the satisfaction that comes from productive reasoning. Experimental Procedure In this experiment, it is essential that all equipment be clean and dry, because 1.8 mL of water is enough to destroy all of the Grignard reagent made in this reaction. Also, since the synthesis of the Grignard reagent is autocatalytic, even traces of water can impede the reaction significantly. Place 2.4 g of magnesium turnings and a small magnetic stir bar in a dry 250-mL round-bottom flask and attach a greased adapter, addition funnel, and condenser (drying tube is optional). Mix well 11.0 mL of butyl bromide and 60 mL of anhydrous ether in the addition funnel and add approximately 10 mL of this solution to the reaction flask. The reaction should begin in a few minutes, as evidenced by gentle refluxing of the solvent. The remaining alkyl halide should be added slowly to maintain the reaction at a stable refluxing rate. This should take about 12 minutes. When the reaction appears to subside, the flask may be warmed for another five minutes by a warm water bath to complete the preparation of the butylmagnesium bromide. At this point, the reaction flask should be cooled by the application of a pan of crushed ice. Into the addition funnel is put 8 mL of dry acetone or propionaldehyde followed by 10 mL of dry ether. This should be swirled briefly and added dropwise over a 30-minute period to the cold Grignard solution. Be sure that the ether is condensing in the condenser during this addition. After the carbonyl compound has been added, the reaction is allowed to warm to room temperature while stirring for another 20 minutes. (This is the point where added aldehyde or alcohol can shift the equilibrium). Prepare 40 mL of 3.0 M hydrochloric acid1 and add about 30 mL of it to 30 g of ice in a large beaker. Carefully decant your reaction mixture into this cold acid in the hood. Rinse the reaction flask with the remaining aqueous acid followed by 20 mL of ether. Add both of these washings and the reaction mixture to a separatory funnel and drain the aqueous layer back into the beaker. Drain and reserve the organic layer, which contains most of the product. Extract any product that is still dissolved in the water layer by dissolving 3–4 g of salt in the water and extracting it twice with 15-mL portions of ether. The aqueous layer may now be discarded. The three combined ether layers should now be washed with 5 mL of cold water, then 5 mL of 10% sodium bicarbon-
Journal of Chemical Education • Vol. 76 No. 1 January 1999 • JChemEd.chem.wisc.edu
In the Laboratory
ate, and finally 5 mL of saturated sodium chloride solution. Dry the ether layer well over anhydrous potassium carbonate and filter it into a distilling flask. Carefully distill the material, collecting the fraction boiling above 120°. An IR spectrum should be taken of the product and all major peaks should be identified. Epilogue The carbonyl peak in the IR spectrum cannot easily be missed or misinterpreted. Further analysis of the spectrum is not productive, but the low-boiling propionaldehyde is not a likely impurity in the distilled product. Instrumental analysis (GC-MS is most informative and easy) and deductive thinking are assisted on an individual basis. Students are then encouraged (but not required) to design an experiment to test
their ideas. Excess propionaldehyde and longer reaction times are the most common suggestions, but other ideas are also pursued. I will be happy to furnish any further details or suggestions that may be desired. Note 1. 100 mL of a 25% aqueous solution of ammonium chloride should be substituted for the hydrochloric acid when making tertiary alcohols.
Literature Cited 1. Touchette, K. M.; Weiss, H. M.; Rozenberg, D. J. Chem. Educ. 1994, 71, 534. 2. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part B: Reactions and Synthesis, 3rd ed.; Plenum: New York, 1990.
JChemEd.chem.wisc.edu • Vol. 76 No. 1 January 1999 • Journal of Chemical Education
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