In the Laboratory edited by
The Microscale Laboratory
R. David Crouch Dickinson College Carlisle, PA 17013-2896
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Iodolactonization of 4-Pentenoic Acid R. David Crouch,* Alexander Tucker-Schwartz, and Kathryn Barker Department of Chemistry, Dickinson College, Carlisle, PA 17013-2896; *
[email protected] Electrophilic addition to alkenes represents a key component of the sophomore-level organic chemistry curriculum. Many lab experiments provide students with an opportunity to replicate reactions found in textbooks. Such experiments include bromination (1), hydrobromination (2), hydroboration-oxidation (3), and acid-catalyzed addition of H2O (4) to alkenes. While valuable, all of these activities involve reactions that are included in the majority of textbooks and students can readily predict the result of the experiment. Activities requiring students to extend their understanding of the course content to explain the outcome of reactions more closely replicate the research experience. The iodolactonization of an alkenoic acid is one such experiment and herein we describe our version of such a lab activity. Experiment Iodolactones typically form when an alkenoic acid is treated with I2, although other sources of iodine have been described. A recent publication describes the use of KI and Oxone (the trade name for potassium peroxymonosulfate) to form I 2 in situ and subsequent iodolactonization of alkenoic acids (5). In our adaptation of this experiment, 4pentenoic acid is converted into the 5-iodo-γ-valerolactone after stirring in water at room temperature in the presence of in situ-generated I2:
This experiment begins by adding Oxone, an oxidant, to an aqueous solution of KI, which produces I2 in situ. Although solid KI兾I2 could be used, we have found this method of in situ production of I2 to be a rapid and easy illustration of generating a reagent in the reaction flask. It is also noteworthy that iodolactonization reactions using the more traditional methods of I2兾NaHCO3 have been observed to be slower reactions, producing lower yields of product that often require chromatographic purification (6). After the oxidation of I− to I2 is complete (less than 10 min), 4-pentenoic acid is added directly to the aqueous mixture. After an hour of stirring at room temperature, workup involves washing with saturated sodium thiosulfate to remove excess I2, extraction with CH2Cl2, drying with MgSO4, filtration to remove the drying agent, and evaporation of solvent. Typical student yields of 5-iodo-γ-valerolactone ranged from 11–89% with an average yield of 63%. www.JCE.DivCHED.org
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Hazards All of the compounds used in this experiment are considered irritants. Oxone is a strong oxidizer and 4-pentenoic acid is toxic and corrosive. CH2Cl2 and chloroform-d are toxic and cancer-suspect agents. [Editor’s Note: A CLIP is available in J. Chem. Educ. for CH2Cl2 (2004, 81, 1415).] Discussion Most students recognize that I2 has formed in the reaction flask and will add to the alkene in much the same fashion as Br2 or Cl2. Although I− and H2O are commonly identified as nucleophilic agents that could attack the iodonium ion, the absence of an OH absorbance in the IR spectrum can be used to lead students to conclude that an iodohydrin did not form and the carboxylic acid failed to survive the reaction. Students were asked to identify possible nucleophiles in the reaction mixture and predict the products of attack of each on the iodonium ion intermediate. A comparison of these possible products with the functional groups indicated by the IR spectrum led most students to conclude that the carboxylic acid’s OH acted as an intramolecular nucleophile. This affords an opportunity to discuss the kinetic advantages of intramolecular over intermolecular pathways. The site of nucleophilic attack on the iodonium ion can be determined by examining the NMR spectrum (7). If the nucleophile attacks at the more substituted carbon—as predicted by Markovnikov’s rule, the ratio of integrations of the signal for the hydrogen on the ester carbon to the signal for the hydrogens on the iodine-bearing carbon should be 1:2. But, if attack occurs at the less substituted carbon, the ratio would be reversed. Examination of the signals centered at 4.55 and 3.36 ppm reveals that the five-membered lactone forms in accord with Markovnikov’s rule.
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The NMR spectrum contains an additional aspect that can be considered by more advanced students. The signal centered at 3.36 ppm is assigned to CH2I but is actually two separate doublet of doublets. Since the ester’s alkyl carbon is a chiral center, these hydrogens are diastereotopic and nonequivalent. Thus, they appear at different chemical shifts and couple with one another as well as the methine hydrogen on the lactone ring. This experiment is easy to perform but the product is not easily predicted. Although it could be used in the first semester of sophomore-level organic chemistry to introduce Markovnikov’s rule, we chose to include this experiment at the beginning of the second semester as a puzzle that requires students to apply concepts from the first semester to solve an unknown reaction mechanism. In fact, with the large excess of H 2O present, most students predicted that an iodohydrin would be the product. Students are required to apply their understanding of the chemical behavior of the reactants and their analysis of the infrared and 1H NMR spectrum to arrive at the product’s structure. Acknowledgments This project was supported by an award to Dickinson College under the Undergraduate Biological Science Education Program of the Howard Hughes Medical Institute. Supplemental Material Instructions for the students and notes for the instructor are available in this issue of JCE Online. W
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Literature Cited 1. (a) Mayo, D. W.; Pike, R. M.; Trumper, P. K. Microscale Organic Laboratory 3rd ed.; John Wiley: New York, 1994; pp 525–529. (b) Williamson, K. L. Macroscale and Microscale Organic Experiments, 4th ed.; Houghton Mifflin: Boston, 2003, pp 658–660. (c) Lehman, J. W. Multiscale Operational Organic Chemistry: A Problem-Solving Approach to the Laboratory Course; Prentice-Hall: Upper Saddle River, NJ, 2002; pp 181–187. 2. (a) Porter, D. J.; Stewart, A. T.; Wigal, C. T. J. Chem. Educ. 1995, 72, 1039–1040. (b) Greenburg, F. H. J. Chem. Educ. 1985, 62, 638. 3. (a) Wigal, C. T.; Hopkins, W. T.; Ronald, B. P. J. Chem. Educ. 1991, 68, A299. (b) Mayo, D. W.; Pike, R. M.; Trumper, P. K. Microscale Organic Laboratory, 3rd ed.; John Wiley: New York, 1994; pp 252–259. 4. Gilbert, J. C.; Martin, S. F. Experimental Organic Chemistry: A Miniscale and Microscale Approach; Harcourt College: Fort Worth, TX, 2002; pp 353–356. 5. Curini, M.; Epifano, F.; Marcotullio, M. C.; Montanari, F. Synlett. 2004, 368–370. 6. Royer, A. C.; Mebane, R. C.; Swafford, A. M. Synlett. 1993, 899–900. 7. Detty, M. R.; Higgs, D. E.; Nelen, M. I. Org. Lett. 2001, 3, 349–353.
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