Laboratory Experiment pubs.acs.org/jchemeduc
Solvent-Free Reductive Amination: An Organic Chemistry Experiment Steven W. Goldstein* and Amely V. Cross† Department of Chemistry, University of Saint Joseph, 1678 Asylum Avenue, West Hartford, Connecticut 06117-2791, United States S Supporting Information *
ABSTRACT: The reductive amination reaction between an amine and an aldehyde or ketone is an important method to add an additional alkyl group to an amine nitrogen. In this experiment, students react a selection of benzylamines with aldehydes to form the corresponding imines. These imines are reduced with a mixture of p-toluenesulfonic acid monohydrate and sodium borohydride to afford dibenzylamines in good yields. Comparison of the melting points of the hydrochloride salts with a set of known melting points is used identify the amine−aldehyde coupling partners. Formation of the product is also confirmed using NMR spectroscopy. KEYWORDS: Second-Year Undergraduate, Organic Chemistry, Alkylation, Amines/Ammonium Compounds, Green Chemistry, Synthesis, Laboratory Instruction
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the undergraduate level.20 Solventless mixing of reagents is often accomplished by melting, microwave irradiation, or, as in this example, grinding. Although students are initially mystified by the lack of solvent, they quickly come to appreciate the more environmentally friendly conditions. Many of the reagents used to effect the reductive step are not suitable for an undergraduate chemistry laboratory. Hydrogenation of the carbon−nitrogen double bond would raise many safety issues and employ expensive catalysts. Sodium cyanoborohydride (NaBH3CN), a now classic reducing agent,21 contains toxic cyanide and would be problematic in a laboratory exercise where acidic solutions are also utilized. Metal- or amino-complexed borohydride reagents22−26 are typically more expensive, require a solvent, often require additional purification, and have varying degrees of selectivity. The use of NaBH4 with added acid27 in a solvent-free reaction fulfills all of the requirements for a safe, efficient, and low-cost experiment.
INTRODUCTION The reductive amination reaction1,2 between a carbonyl and an amine is both useful and versatile. During the course of the reaction (Scheme 1), a carbonyl component, either a ketone (1) or an aldehyde (2), condenses with an amine (3) to produce an imine (4) or iminium ion, depending on the amine substitution. This intermediate can be reacted with a variety of nucleophiles, including organometallics3−5 and cyanide,6 as well as oxygen-7 and nitrogen-containing8 groups. Alternatively, reduction of the carbon−nitrogen double bond with hydrogen,9 hydride,10,11 or a source of electrons12 produces the more highly functionalized amino product (5). The utility of this reaction is far reaching; a recent survey13 found that over 90% of small molecule drug candidates from the pharmaceutical industry contain nitrogen. Functionalization of the nitrogen via reductive amination occurs in about 20% of the chemical syntheses of these compounds. The reductive step may proceed to give either a symmetric methylene group (resulting from an aldehyde and amine) or a new chiral center (resulting from a ketone and an amine). The addition of various chiral ligands can give enantioenriched products.10,14 Reductive aminations have been extensively reviewed,1 in both the symmetric and asymmetric pathways.15 Surprisingly, there are only two reported laboratory experiments in this Journal involving this reaction.16,17 In both of these experiments, a single product is made. Herein, a solvent-free reductive amination experiment is described where students identify the product (and starting components, vide infra) from a panel of possible products based on the melting point of the product hydrochloride salt. The use of solvent-free reaction conditions is an important tenet of green chemistry;18 its utilization is evident in both academic and industrial19 arenas, as well as at © XXXX American Chemical Society and Division of Chemical Education, Inc.
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EXPERIMENT Students may work alone or with a single lab partner. This laboratory exercise can easily be done in a single 3 to 4 h lab session. Students select a benzaldehyde−benzylamine (Scheme 2) combination and mix the reagents together in roughly equimolar amounts in an agate mortar and pestle to produce the intermediate imine. In many cases, the imine forms a solid or slurry; this easily observable physical change, which takes place without solvent, is instrumental for students to determine that a reaction is taking place. Following formation of the imine, a premixed, equimolar amount of p-toluenesulfonic acid
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DOI: 10.1021/ed5006618 J. Chem. Educ. XXXX, XXX, XXX−XXX
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Laboratory Experiment
Scheme 1. Imine Formation and Reduction
reactions were complicated with unreacted starting material, and, therefore, the four benzaldehydes and two benzylamines used in the experiment were liquids. Additionally, the hydrochloride salts of the dibenzylamine products must be crystalline and form quickly, and their melting points must be different enough that students can make accurate comparisons. Students typically isolated the dibenzylamine product as an oil following evaporation of the dried ethyl acetate extraction in 57−85% yield. Formation of the hydrochloride salt with a slight molar excess of HCl in water/ethanol occurred rapidly in every example; recrystallization from ethanol provided crystalline material in every case, which was characterized by 1H and 13C NMR spectroscopy (vide supra). The yields of purified salts were in the range of 8−32%, based on starting material, and typically had a 2 °C melting point range. All but one group of students had melting points that overlapped with the expected values and correctly identified the product and corresponding starting materials. Based on pre- and postlaboratory questions, 94% of students could correctly predict the products of a reductive amination when asked to supply the ketone structures of their own choosing. All students understood why the addition of the reducing agent should be done after formation of the imine was complete.
Scheme 2. Formation of Dibenzylamines
monohydrate and sodium borohydride (equimolar with the imine) is added and the reaction mixed in the mortar and pestle for an additional 30 min. Conversion to the amino product is often accompanied by the formation of a solid with a different texture. Partitioning the mixture between aqueous 5% NaHCO3 and ethyl acetate, followed by concentration of the organic layer, gives the desired crude reductive amination product. Definitive structural identification of the oily dibenzylamines is problematic with a low-field 1H NMR spectrometer due to overlapping signals in the spectra. Alternatively, the secondary amines are readily converted into the non-hygroscopic hydrochloride salts in HCl (aq)/ethanol and recrystallized from hot ethanol; the melting points are compared against a list of known melting points for identity. It is best to allow the product to dry overnight to remove traces of solvent before the melting point determination. The conversion of the aldehyde into the reductively aminated product was seen in both 1H NMR (loss of the aldehyde proton) and 13C NMR (observation of two benzyl amine resonance signals near 50 ppm). A detailed description of the experiment is in the Supporting Information.
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SUMMARY This student experiment allowed for the solvent-free conversion of a benzylamine and an aldehyde into an imine, with an observable physical change. Treatment with a reducing agent effected the reductive amination, the product was characterized by conversion into the corresponding hydrochloride salt, and the melting point was compared to a standard set of data. Students were then able to identify the aldehyde− amine combination that they utilized.
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ASSOCIATED CONTENT
S Supporting Information *
HAZARDS Ethyl acetate and ethanol are flammable, as well as inhalation and contact hazards. Hydrochloric acid and p-toluenesulfonic acid monohydrate are very corrosive; chemical splash goggles and other forms of PPE (e.g., gloves, aprons) should be worn at all times. Sodium borohydride is flammable and an inhalation and contact hazard; it can react violently with strong acids. The aldehydes, benzylamines, and dibenzylamine products are flammable and should be disposed of following guidelines for organic waste disposal. DMSO-d6 is a contact hazard and flammable and should be disposed of following guidelines for organic waste disposal.
A detailed student handout of the experiment and instructor notes. This material is available via the Internet at http://pubs. acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Present Address † A.V.C.: Asnuntuck Community College, 170 Elm St., Enfield, CT 06082.
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Notes
RESULTS AND DISCUSSION Eighteen students in two laboratory sections in a secondsemester introductory organic chemistry course have completed this experiment. The selection of both the amine and carbonyl components was critical for the success of the experiment; if one or both of the components were solid, the
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful to the Spring 2014 Chem 210 laboratory classes for data and feedback. B
DOI: 10.1021/ed5006618 J. Chem. Educ. XXXX, XXX, XXX−XXX
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