In the Laboratory
Counterion Effects in the Nucleophilic Substitution Reaction of the Acetate Ion with Alkyl Bromides in the Synthesis of Esters Elizabeth M. Valentín and Ingrid Montes* Department of Chemistry, University of Puerto Rico-Río Piedras Campus, San Juan, Puerto Rico 00931; *
[email protected] Waldemar Adam Institute of Organic Chemistry, University of Würzburg, Am Hubland, D-97094 Würzburg, Germany and Department of Chemistry, University of Puerto Rico-Río Piedras Campus, San Juan, Puerto Rico 00931
Aside from their utility as synthetic intermediates, esters are often employed as artificial flavorings in foods and drinks because the more volatile ones possess distinctive odors characteristic of common fruits (1–4). A sampling of esters found in fruits is shown in Table 1. A laboratory experiment that introduces students to the esterification method is presented, which can be performed in a few hours. A simple ester is synthesized, its yield determined by analyzing the recovered mass by gas chromatography (GC), and its identity assessed by mass spectrometry (MS). Most student experiments on esterification (5–14) emphasize the Fischer method in which a carboxylic acid is condensed with the required alcohol (6–9, 14). Alternatively, the desired ester may be synthesized by a nucleophilic substitution reaction (SN2 or SN1) between an alkyl halide and a metal carboxylate (15–17). This is the approach chosen for the present experiment. This method is rarely used in the organic chemistry teaching laboratory; however, it may be employed to introduce students to important concepts. In particular, students learn that the metal counterion plays an important role with regard to the efficiency of the reaction and that the ester yield depends on the type of mechanism, namely, whether an SN2 or SN1 process occurs.
In addition, the results can be explained in terms of Pearson’s hard and soft acid–base principle (HSAB), an empirical concept rarely used in introductory organic chemistry (18). The HSAB principle classifies acids and bases as hard or soft, according to their polarizability. For example, a cation with a high positive, non-polarizable charge is considered a hard acid, whereas a cation with a polarizable charge is a soft acid. Bases are defined accordingly, except one deals with negatively charged ions. The HSAB principle states that a hard acid reacts preferably with a hard base, whereas a soft acid favors a soft base. The nucleophilic substitution reaction is one of the first transformations taught in introductory organic chemistry (18–21) because of its straightforward mechanism (SN1 versus SN2) and the convenience and simplicity of conducting it in the laboratory. While the effects of the substrate, leaving group, nucleophile, and reaction conditions are extensively covered, the influence of the metal counterion of the nucleophile has received little attention. The current experiment follows a guided-inquiry approach in which the students explore the effect of the metal counterion on the product yield. Because the observed trends in the ester yields are interpreted in terms of the HSAB principle, students become exposed to a useful theory by conducting this experiment (18, 22–24). Experiment
Table 1. Names, Structures, and Fruit and Flower Aromas of Some Common Natural Esters Ester Name
Structure O
3-Methylbutyl acetate
n-Octyl acetate
Bananas
O O
n-Butyl acetate
Aroma
Pears
O O
Oranges
O O
Benzyl acetate
Peaches
O O
Benzyl butyrate
Ethyl butyrate
Flowers*
O O O
Pineapples
*Jasmine with a fruity character reminiscent of rose and apricot.
This experiment may be conducted individually or with student pairs. It should ideally be performed over two laboratory periods. The first period deals with synthesis and the second period with analysis and interpretation of the results. Each student or student pair prepares one of three esters, namely, 3-methylbutyl, n-octyl, or benzyl acetate, that were chosen because of their recognizable aromas (Scheme I). Each student (or student pair) is assigned one alkyl bromide as a substrate and either the lithium, sodium, potassium, or cesium acetate salt. An equal number of students (or student pairs) synthesize banana (3-methylbutyl acetate), orange (n-octyl acetate), and peach (benzyl acetate) flavors. The results for all twelve possible reactions are pooled so that the students may reach definitive conclusions concerning the effect of the metal counterions on the product yields. Procedure A 50 mL, round-bottom flask is charged with the metal acetate salt (18.0 mmol), acetic acid (9 mL), and alkyl bromide (12.0 mmol). The flask is equipped with a reflux condenser, and the reaction mixture heated under reflux for 90 min. The heat source is removed, and the reaction mixture is allowed to cool
© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 86 No. 11 November 2009 • Journal of Chemical Education
1315
In the Laboratory O O
Br
O ∙ O∙ M
Br
acetic acid (solvent)
Br
M = Cs, Na, K, Li
O
O
O
O Scheme I. Esters synthesized by the nucleophilic substitution reaction of alkyl bromides with metal acetates.
to room temperature. Sufficient saturated aqueous solution of NaHCO3 is added to neutralize the acetic acid (until pH paper tests alkaline). The product mixture is extracted with ethyl ether (2 × 10 mL), and the combined organic phases are dried over anhydrous MgSO4. The drying agent is removed by filtration. The solvent is evaporated with the help of a warm (about 45 °C) water bath, and the dry crude product is collected and weighed to determine the yield. The purity and identity of the ester product is assessed by thin-layer chromatography (TLC) (using alumina gel and 9:1 n-hexane:ethyl acetate) and by GC– MS analysis. Hazards Students must consult the relevant MSDS before conducting the experiment. The alkyl bromides are irritants and flammable liquids. Benzyl bromide is a lachrymatory liquid and acetic acid a corrosive substance, neither of which must be inhaled. Ether, ethyl acetate, and hexane are flammable liquids and harmful if inhaled or if exposed to skin. The metal acetates are hygroscopic and cause skin irritation. Students must wear safety goggles and gloves at all times and work in a wellventilated hood.
ester is needed to assess the degree of success of the reaction. TLC provides a quick and simple check of purity. A more sophisticated method entails GC–MS analysis. The yield of the product is determined by using the mass of the recovered crude material and the purity of the ester determined by GC analysis (Table 2). If the necessary instrumentation is not available, this analysis is conducted by contracting the services of experts. A sample chromatogram is given in Figure 1, together with the pertinent mass spectra. The results presented concur with the student data. Discussion The quantitative data in Table 2 exhibit some definitive trends that reflect the strong interplay between the bromide ion leaving group in the substrate and the acetate ion nucleophile in the metal salt as a function of the metal ions Cs+, K+, Na+, and Li+. For example, the ester yields of the substrates 3-methylbutyl
Table 2. Yields of Ester Product as a Function of Metal Counterion Ester Product
Yield (%) Cesium
Potassium
Sodium
Lithium
Results
3-Methylbutyl
76
58
21
8
The pleasant, fruity odor detected during workup reveals the identity of the ester product. Precipitation of a solid metal bromide salt indicates a successful experiment; however, whereas CsBr and KBr readily precipitate, NaBr does so rarely and LiBr not at all. As a result, this visual indicator is not a reliable measure of success. Instead, isolation and quantification of the
n-Octyl
78
40
22
13
Benzyl
76
76
84
>95
1316
Note: The yields were obtained by multiplying the gravimetric yields of the crude product by the relative areas (uncorrected) of the GC peaks; the gravimetric yields were determined by weighing the isolated, crude product; error limits are about 5% of the stated values.
Journal of Chemical Education • Vol. 86 No. 11 November 2009 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Laboratory A
Total Ion Current (Arbitrary Unit)
60 R–Br 10.94 min 47.2% abundance
50
R–OAc 12.34 min 52.8% abundance
40
30
20
10
0 6
8
10
12
14
16
Retention Time / min B
Relative Abundance (%)
100
Br
80
193.12 amu 60
40
20
0 60
80
100
120
140
160
m/z C
100
Relative Absorbance (%)
and n-octyl bromides follow the order Cs+ > K+ > Na+ > Li+, with cesium acetate the highest and lithium acetate the lowest product. This pronounced metal counterion effect illustrates the efficacy of the HSAB principle. These two alkyl bromides are typical SN2 substrates. The bromo substituent at the reaction center is a weak electron-attracting group, which imparts a low electrophilic character to the Br-substituted carbon atom; thus, this carbon center is a relatively soft acid (electrophile) in want of a soft base (nucleophile) for best interaction. The attacking acetate ion, however, is a relatively hard base (nucleophile), whose reactivity is modulated by the accompanying metal counterion, for which the degree of softness follows the order Cs+ > K+ > Na+ > Li+. The acetate nucleophile is a softer base—therefore a better nucleophile—when combined with Cs+ as a counterion than with Li+. The cesium acetate salt (the combination of the soft Cs+ metal counterion with the hard acetate nucleophile) is more dissociated in solution than lithium acetate salt (the combination of the hard Li+ counterion with the hard acetate nucleophile). The more dissociated the salt, the softer a base the acetate ion will be and more reactive towards the SN2-type alkyl bromide substrate (softer acid). The expected reactivity would be CsOAc best and LiOAc worst, as revealed by the observed yields in Table 2 (25). However, the opposite trend is observed for the benzyl bromide substrate, for which the yields follow the order Cs+ Cs+ as observed (Table 2). Thus, the set of chosen alkyl bromide substrates not only offers the opportunity to probe the metal counterion influence in nucleophilic substitution reactions but also accentuates the mechanistic nuances of the SN2–SN1 reactivity in terms of the HSAB concept.
O O
80
172.26 amu 60
40
20
0 60
80
100
120
140
m/z
Summary A straightforward experiment is offered to the students; to learn how to conduct an organic synthesis (a natural ester of fruit flavors), apply previously acquired laboratory techniques (extraction, filtration, TLC, GC, etc.), and employ modern instrumental methods (GC–MS analysis) for determining the purity and identity of the isolated esters. Moreover, the instructor has the opportunity to assess the students’ dexterity in perform-
Figure 1. The chromatogram of the crude product mixture for the reaction of n-octyl bromide with potassium acetate is given in panel A, in which the retention times and the uncorrected relative peak areas are listed; the relative peak areas were determined for each component from the total ion current of the mass-selective detector (OAc = acetate). The mass spectra of the two GC components are shown in the panels B and C, identified, respectively, as n-octyl bromide and n-octyl acetate.
© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 86 No. 11 November 2009 • Journal of Chemical Education
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In the Laboratory
ing these practical skills, as well as test the students’ competence in mass-spectral interpretation. Most significantly, to understand mechanistically the observed trends in the product yields, the students are introduced to Pearson’s HSAB principle. In the present case, this principle rationalizes the effect of the metal counterion on the reactivity of the acetate nucleophile towards alkyl bromide substrates. Discussion questions, experimental results, and in-class discussion guide the students to a more thorough understanding of this concept. The student feedback on this engaging and innovative laboratory exercise has been positive, as confirmed by the complimentary comments. Acknowledgments We gratefully acknowledge Dr. Prieto’s help with the cesium reagent, Drs. Sanabria and Carballeira for their assistance with the GC–MS analysis. We also thank the students of the 2006–2007 organic chemistry course for their constructive feedback during the implementation of this experiment. W.A. acknowledges the generous financial support from the Deutsche Forschungsgemeinschaft, Alexander von Humboldt-Stiftung, and the Fonds der Chemischen Industrie. Literature Cited 1. Crocker, E. C. J. Chem. Educ. 1945, 12, 567–569. 2. Eskew, R. J. J. Chem. Educ. 1951, 18, 326–327. 3. Clarke, M.; Brown, A.; Epp, D. N.; Gallup, M.; Wilson, J. R.; Wuertherle, J. A. J. Chem. Educ. 1986, 63, 1050–1051. 4. Taylor, A. J. Comp. Rev. Food Sci. Food Safety 2002, 1, 45–57. 5. Puterbaught, W. H.; Vanselow, C. H.; Nelson, K.; Shrawder, E. J. J. Chem. Educ. 1963, 40, 349–350. 6. Hocking, M. B. J. Chem. Educ. 1980, 57, 527. 7. Williamson, K. L. Macroscale and Microscale Organic Experiments, 1st ed.; D. C. Heath and Company: Toronto, 1989; pp 302–314. 8. Birney, D. M.; Starnes, S. D. J. Chem. Educ. 1999, 76, 1560–1561. 9. Whitlock, C. R.; Bishop, P. A. Chem. Educator 2003, 8, 352. 10. Duarte, R.; Nielsen, J. T.; Dragojlovic, V. J. Chem. Educ. 2004, 81, 1010–1015.
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11. Lee, S. Chem. Educator 2004, 9, 359–363. 12. Van den Berg, A. W. C.; Itanefeld, U. J. Chem. Educ. 2006, 83, 292–293. 13. Montes, I.; Sanabria, D.; García, M.; Castro, J.; Fajardo, J. J. Chem. Educ. 2006, 83, 628–631. 14. Wade, P. A.; Rutkowsky, S. A.; King, D. B. J. Chem. Educ. 2006, 83, 927–928. 15. Brown, D. P.; Durutlic, H.; Juste, D. J. Chem. Educ. 2004, 81, 1016–1017. 16. Stabile, R . G.; Dicks, A. P. J. Chem. Educ. 2004, 81, 1488–1491. 17. Clennan, M. M.; Clennan, E. L. J. Chem. Educ. 2005, 82, 1676–1678. 18. Pearson, R. G. J. Org. Chem. 1987, 52, 2131–2136. 19. Anderson, M. M. J. Chem. Educ. 1987, 64, 1023–1024. 20. Wright, S. W. J. Chem. Educ. 1992, 69, 235–237. 21. Sun, X. Chem. Educator 2003, 8, 303–306. 22. Daley, R. F.; Daley, S. J. Organic Chemistry 2003, pp 209–242. http://www.ochem4free.com (accessed Apr 2009). 23. Pearson, R. G. J. Chem. Educ. 1987, 64, 561–567. 24. Ho, T. L. J. Chem. Educ. 1978, 55, 355–360. 25. Smith, M.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th ed.; John Wiley & Sons, Inc: New York, 2007; pp 375–380, 516.
Supporting JCE Online Material
http://www.jce.divched.org/Journal/Issues/2009/Nov/abs1315.html Abstract and keywords Full text (PDF) with Links to cited URL and JCE articles Supplement
Instructions for the students including pre-laboratory and discussion questions
Notes for the instructor
JCE Featured Molecules for November 2009 (see p 1344 for details) Structures of some of the molecules discussed in this article are available in fully manipulable Jmol format in the JCE Digital Library at http://www.JCE.DivCHED.org/JCEWWW/Features/ MonthlyMolecules/2009/Nov/.
Journal of Chemical Education • Vol. 86 No. 11 November 2009 • www.JCE.DivCHED.org • © Division of Chemical Education
