In the Laboratory
A Safer, Discovery-Based Nucleophilic Substitution Experiment Gail Horowitz Department of Chemistry, Yeshiva University, New York, NY 10033;
[email protected] Nucleophilic substitution is a fundamental reaction covered in undergraduate organic chemistry. When introduced to this topic, students typically learn that substitution proceeds via one of two mechanisms, either SN1 (uni-molecular) or SN2 (bi-molecular). However, the study of this reaction also introduces students to many additional and important concepts, including how the structure of a substrate can affect the stereochemistry of the reaction and how the nature of a nucleophile can affect the rate of the reaction. A few nucleophilic substitution experiments have been published in the literature (1–6), including a well-known “Competing Nucleophiles” experiment (7–9) in which students compare the reactivity of a primary and tertiary alcohol in the presence of a one-to-one mixture of chloride to bromide ion. This experiment allows students to both examine the effect of nucleophilicity on the reaction rate, as well as the effect of substrate structure on the outcome of the reaction. For many years, students at this university conducted the “Competing Nucleophiles” experiment, first on the macroscale and later on a microscale. And while the “Competing Nucleophiles” experiment was an excellent discovery-based experiment and excellent teaching tool, some faculty and students were uneasy because this reaction generated small quantities of hydrogen chloride and hydrogen bromide gas.1 Experiment As a result, a safer nucleophilic substitution experiment that could provide students with the same degree of intellectual challenge as the “Competing Nucleophiles” experiment was developed. The following Finkelstein reaction (10), in which a quaternary phosphonium salt (hexadecyltributylphosphonium, HDTBPB) is used as the phase-transfer catalyst and KX is either KCl or KI, was used: CH (CH ) CH 3 26 2
Br
KX (aq sat) HDTBPB 1 h; 60 pC
and to present an explanation of how their catalyst worked in the reaction and why it was needed. Hazards This experiment should be conducted under a fume hood. Gloves should be worn. The octyl halides and the phosphonium salt used in this experiment are irritants. However, the toxicological effects of octyl chloride have not been fully studied. Results and Analysis In order for students to obtain reasonable results in this experiment, it is important that they stir their reaction mixtures vigorously, as this is a two-phase reaction. It is also important that no product escape during the heating process, as the chloride product is more volatile than the bromide reactant, which is more volatile than the iodide product. As a precaution, students use a septum-capped (but needle vented), water-cooled condenser when conducting this reaction. The students obtain reasonable results by simply measuring the refractive index of their crude product (which is contaminated with the phosphonium salt). By then assuming that their crude product contains only n-octyl bromide and the n-octyl halide product, students can use the linearity of the relationship between refractive index and mole percent n-octyl bromide to estimate what percent starting material remains in their reaction (see the online material for instructions).3 Alternatively, students can remove the phosphonium salt by dissolving their product in pentane and then filtering the resulting solution (under pressure) through a short column of flash grade silica gel (11). After filtration, students can use gas chromatography to determine the percent product and percent starting material for the two reactions. Learning Outcomes
CH3(CH2)6CH2
X
In this experiment, students react n-octyl bromide with either chloride or iodide ion, but stop the reaction before it goes to completion. (In the course of one hour, the iodide reaction is about 90% complete, whereas the chloride reaction is about 30% complete.) Using either refractive index or gas chromatography, students then determine the extent to which their reactions have gone to completion. For their data analysis, students are asked to compare the results of the two reactions and to draw conclusions as to why one nucleophile reacted faster than the other.2 Students are also asked to hypothesize about what type of results they would have obtained had they used a tertiary substrate, instead of a primary one. Additionally, students are required to briefly research the topic of phase-transfer catalysis
Because this experiment was timed to coincide with when students learned about nucleophilic substitution in their lecture course, we found that the average student could readily explain the difference in reaction rate between chloride and iodide. Typically, students did so by discussing the size or the strength of the nucleophile. Some students mentioned polarizability. In line with a discovery approach, students were expected to read up on phase-transfer catalysis on their own and explain the function of the phase-transfer catalyst in their reaction. We found that most students were correctly able to explain the role of the phase-transfer catalyst (to “shuttle” the nucleophile to the organic layer) and that they understood the problem of the insolubility of the nucleophile in the organic phase. However, a number students were not able to properly explain how the catalyst does its job (how it is able to bind the nucleophile and dissolve in the organic phase).
© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 86 No. 3 March 2009 • Journal of Chemical Education
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In the Laboratory
Conclusion Using a phase-transfer catalyst, students are able to safely conduct a “Competing Nucleophiles” type experiment in which they discover a difference in reactivity between two halide nucleophiles. This experiment also asks them to consider under what conditions (SN2 or SN1) does nucleophilicity affect the rate of a reaction. Notes 1. Although the “Competing Nucleophiles” experiment called for the trapping of these gases, we have found trapping not to be effective, especially in the hands of students. 2. Students obtain the results of a classmate who used the other nucleophile. 3. The experiment has been conducted using the refractive index of their crude product for three semesters.
Acknowledgment The author would like to acknowledge and thank Jacob Herman for his assistance in the development and testing of this experiment. Literature Cited 1. Clennan, M. M.; Clennan, E. L. J. Chem. Educ. 2005, 82, 1676– 1678.
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2. Howell, B. A.; Kohrman, R. E. J. Chem. Educ. 1984, 61, 932– 934. 3. Kjonaas, R. A.; Tucker, R. J. F. J. Chem. Educ. 2008, 85, 100–101. 4. Pace, R. D.; Regmi, Y. J. Chem. Educ. 2006, 83, 1344–1348. 5. Shepherd, J. N.; Stenzel, J. R. J. Chem. Educ. 2006, 83, 425–427. 6. Williamson, K. Macroscale and Microscale Organic Experiments, 4th ed.; Houghton Mifflin: New York, 2003; pp 259–273. 7. Ault, A. Techniques and Experiments for Organic Chemistry, 6th ed.; University Science Books: Sausalito, CA, 1998; pp 407–409. 8. Pavia, D. L.; Lampman, G. M.; Kriz, G.; Engel, R. G. Introduction to Organic Laboratory Techniques: A Small Scale Approach, 2nd ed.; Brooks Cole: New York, 2005; pp 174–180. 9. Warren, H. W.; Newton, T. A. J. Chem. Educ. 1980, 57, 747. 10. Cinquini, M.; Montanari, F. J. Chem. Soc. Chem. Comm. 1975, 393–394. 11. Hahn, R. C. J. Chem. Educ. 1997, 74, 836–838
Supporting JCE Online Material
http://www.jce.divched.org/Journal/Issues/2009/Mar/abs363.html Abstract and keywords Full text (PDF) Links to cited JCE articles Supplement
Student handouts, including questions
Instructor notes, including chemicals and equipment needed and GC conditions
Journal of Chemical Education • Vol. 86 No. 3 March 2009 • www.JCE.DivCHED.org • © Division of Chemical Education
