In the Laboratory
Reductive Amination: A Remarkable Experiment for the Organic Laboratory
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Kim M. Touchette Bard College, Annandale-on-Hudson, NY 12504;
[email protected] Amine synthesis is an extremely important reaction for synthetic organic chemists and has enormous applicability for biological molecules and drug discovery. One of the most versatile methods used in the synthesis of structurally diverse primary, secondary, and tertiary amines is reductive amination of carbonyl compounds. Reductive amination is usually described as a one-pot procedure that involves the reaction of an aldehyde (or ketone) with ammonia or primary or secondary amines to form an imine or iminium salt intermediate followed by in situ reduction to an amine of higher order (1). Hydrogen over nickel or a weakened hydride donor is commonly used, as these are slow to reduce the carbonyl reactant. Two of the most widely used reducing agents for reductive amination are NaBH3CN (2) and NaBH(OAc)3 (3). This one-pot reaction is particularly appropriate for the reaction of an aldehyde with ammonia because the primary imines are unstable, readily hydrolyzing to the carbonyl compounds. However the more stable substituted imines, sometimes called Schiff bases, may be isolated especially when one of the substituents is a phenyl group. In this experiment, we form the imine quantitatively in a solvent-free reaction (4) between two solids. The imine is subsequently reduced with sodium borohydride to the amine, followed by acetylation to afford a solid amide derivative. The entire reaction sequence can be performed in one hour in an open beaker. The reaction of two solids is impressive, entertaining, and amazingly efficient. We describe the reaction with orthovanillin and para-toluidine because the color changes are most dramatic (Scheme I). The reaction also works quite well with the less expensive para-vanillin, which, while less dramatic, may be of interest to labs with large enrollments. Several alternative pairings are presented in ref 4b. The vanillins are pale yellow and the para-toluidine should be fairly colorless for observing the dramatic color changes. The simplicity of the method will tempt students to try many other combinations (4b).1 In contrast to typical experimental procedures (5) the reaction is carried out without solvent. Solventless reactions between solids are frequently referred to as “solid–solid” reactions; however it has been noted that in many cases (4c, 6), including this one, mixtures of the solid reactants result in melting, so that the reaction actually occurs in the liquid, albeit solvent-free state. The visible melting that occurs when the two solids are mixed together in this reaction is interesting and can be useful in illustrating to students, in a vivid way, that impurities lead to lowering in the melting point of solids. The synthesis of amines, imines, and amides is central to our understanding of many biological pathways. The experiment presented here provides an opportunity to experience all three reactions in a single laboratory session. The experiment offers several additional advantages, including www.JCE.DivCHED.org
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short reaction times, excellent yields, and environmentally friendly conditions; there are no waste solvents except for aqueous ethanol. In addition, the experiment introduces solid–solid reactions and highlights another key green chemistry concept, specifically, the design of efficient, atom economical reactions with quantitative conversion to the imine product with the only byproduct being water. All of these features make the experiment an attractive addition to the organic chemistry curriculum. Experimental Procedure The carbonyl compound, 0.76 grams (5.0 mmol)2 of ortho-vanillin, and the amine, 0.54 grams (5.0 mmol) of paratoluidine, are combined in a beaker. If the solids are placed on opposite sides of the beaker, the reaction initially occurs at the interface and is quite dramatic. The two nearly colorless starting materials give rise to a bright orange product that is initially visible in a small area where the two reactants are in contact. Following this initial observation the solids should be mixed thoroughly with a glass rod. The low-melting reagents will melt, however within five minutes a dry orange
Scheme I. The reaction with ortho-vanillin and para-toluidine.
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In the Laboratory
powder will be produced. If the beaker has been weighed prior to the addition of the starting materials then the product yield may be determined by simply weighing the beaker and its contents. The yields are quantitative and the product is quite pure.3 Alternatively the imine product may be recrystallized from hexanes to yield orange needles, (mp 102–103 ⬚C.) The imine is subsequently reduced to the amine and then converted to the more stable amide by acetylation. The reduction is accomplished by the addition of ∼15 mL of 95% ethanol4 to the beaker containing the imine followed by the addition of 0.10 grams (2.6 mmol) of sodium borohydride in small increments to the stirred reaction mixture. The imine is only partially soluble in the ethanol, but the product is quite soluble and thus within ten minutes a colorless solution is an indication that the reaction is complete. The amine may be isolated at this point but we chose to convert the amine directly to the corresponding acetamide derivative. The addition of ∼2 mL of glacial acetic acid to the ethanolic solution of the amine will neutralize the basic solution and destroy the excess sodium borohydride. Acetic anhydride (2 mL) is added to the reaction mixture and warmed on a hot steam bath for 5–10 minutes. The amide product precipitates out when 75 mL of cold water is added slowly to a magnetically stirred solution. The product, a colorless solid, is collected by vacuum filtration and analyzed by IR or NMR and melting point. The overall yields typically range from 80–90% overall. A small quantity of the product may be recrystallized from hexanes, (mp 127–128 ⬚C.) Hazards This experiment should be conducted in a well-ventilated hood. Acetic acid and acetic anhydride are corrosive. Acetic anhydride is also a lachrymator. Toluidine is highly toxic and organic amines are potential carcinogens, therefore caution is advised when working with the amines. Conclusion We have presented a remarkably efficient three-part reductive amination sequence, which includes a synthesis of an imine followed by its subsequent transformation to an amine and then an amide derivative. Students have found the reaction fascinating and we have found it very useful in
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illustrating the importance of reductive amination in organic synthesis as well as introducing the concept of green chemistry and solid–solid reaction concepts. We anticipate that this reaction will be a useful addition to the limited pool of amine syntheses for the second-year organic laboratory. Notes 1. The reaction of para-toluidine with piperonal (reagents in ref 5 ) is also feasible but reaction times are significantly longer. 2. The reaction works quite well on half the scale as well as twice the scale. 3. This is dependent upon using equimolar quantities of the reactants. The reaction is noticeably exothermic and appears to assist in the evaporation of the water from the product. 4. Methanol is also an appropriate solvent, we chose the more environmentally friendly ethanol but the reaction works just as well in methanol. W
Supplemental Material
Instructions for the students and notes for the instructor are available in this issue of JCE Online. Literature Cited 1. For reviews of reactions of carbonyl compounds leading to the formation of C⫽N bonds, see Lane, C. F. Synthesis 1975, 135– 146. Hutchins, R. O.; Hutchins, M. K. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1999; Vol. 8, pp 25–78. Baxter, E. W.; Reitz, A. B. Organic Reactions; Wiley: New York, 2002; Vol. 59, pp 1–714. 2. Mattson, R. J.; Pham, K. M.; Leuik, D. J.; Cowen, K. A. J. Org. Chem. 1990, 55, 2552. 3. Abdel–Magid, A. F.; Maryanoff, C. A.; Carson, K. G.; Harris, B. D.; Shah, R. D. J. Org. Chem. 1996, 61, 3849–3862. 4. (a) Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem. Commun. 2001, 21, 2159–2169. (b) Schmeyers, J.; Toda, F.; Boy, J.; Kaupp, G. J. Chem. Soc., Perkin II 1998, 989–993. (c) Rothenberg, G.; Downie, A. P.; Raston, C. L.; Scott, J. L. J. Am. Chem. Soc. 2001, 123, 8701–8708. 5. Carlson, M. W.; Ciszewski, J. T.; Bhatti, M. M.; Swanson, W. F.; Wilson, A. M. J. Chem. Educ. 2000, 77, 270–271. 6. Palleros, D. R. J. Chem. Educ. 2004, 81, 1345–1347.
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