LABORATORY EXPERIMENT pubs.acs.org/jchemeduc
Learning about Regiochemistry from a Hydrogen-Atom Abstraction Reaction in Water Christopher Sears-Dundes,† Yoeup Huon,† Richard P. Hotz,*,† and Allan R. Pinhas*,‡ † ‡
Department of Chemistry, College of Mount St. Joseph, Cincinnati, Ohio 45233-1670, United States Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221-0172, United States
bS Supporting Information ABSTRACT: An experiment has been developed in which the hydrogenatom abstraction and the coupling of propionitrile, using Fenton’s reagent, are investigated. Students learn about the regiochemistry of radical formation, the stereochemistry of product formation, and the interpretation of GC MS data, in a safe reaction that can be easily completed in one laboratory session. KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Aqueous Solution Chemistry, Constitutional Isomers, Diastereomers, Free Radicals, Gas Chromatography, Mass Spectrometry, Stereochemistry
n many organic chemistry textbooks,1 regiochemistry is discussed with respect to addition of a proton to the less substituted side of a double bond. Students can confirm these results in the laboratory by the addition of HX to a substituted ethene derivative. In addition, textbooks discuss abstraction of a hydrogen atom from a saturated hydrocarbon, such as propane, by a bromine or chlorine atom. However, students usually cannot perform this reaction in the laboratory due to the use of toxic halogens and solvents. Fenton chemistry, first discovered in the 1890s,2 oxidizes an organic molecule by the generation of an active radical species from a mixture of a metal and hydrogen peroxide.3,4 Fenton chemistry is well-known for its ability to remove a hydrogen atom from DNA and causing the double helix to unravel. It also causes the degradation of other biological systems such as proteins and lipids. This reaction can be demonstrated with the decoloration of green food coloring.5 Fenton’s original publication dealt with the decomposition of tartaric acid. In contrast, there are very few publications in which Fenton chemistry is used to synthesize new molecules. In the Fenton coupling reaction discussed in this article, students explore the regiochemistry of hydrogen-atom abstraction using readily available and nontoxic reagents with water as the solvent. In this experiment, students learn about hydrogen-atom abstraction and coupling reactions, as well as, resonance stabilization, stereochemistry, regiochemistry, and mass spectroscopic identification of isomeric products. The experiment can be easily completed in one laboratory session. Specifically, the coupling reaction of water-soluble propionitrile using Fenton’s reagent (Fe(II) and H2O2 with a drop of H2SO4) is described. The best yields of the coupling products are
obtained when the concentration of the metal is kept low.4,6 Hydrogen-atom abstraction is selective, preferentially producing the radical R to the nitrile. Although there is disagreement in the literature regarding the mechanism of this reaction,3,4 it really does not matter if a free radical or an iron oxo complex is formed. What matters is that the Fenton chemistry generates a radical or radical-equivalent that can remove a hydrogen atom from the alkyl chain of the alkyl nitrile, and then two of these “alkyl radicals” couple.6 Fenton chemistry is environmentally friendly compared to traditional organic laboratory experiments. Iron, the metal reagent, is low in toxicity in small quantities. Oxidation by hydrogen peroxide produces water and oxygen as byproducts. Water is used as the solvent, and because the reaction proceeds with high conversion, there is little organic waste.
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Copyright r 2011 American Chemical Society and Division of Chemical Education, Inc.
’ EXPERIMENT A full experimental section with raw student data, mass spectrometry interpretation, and instructor notes may be found in the Supporting Information. ’ HAZARDS The only hazard with this reaction is students must be careful when using the corrosive chemicals sulfuric acid and hydrogen peroxide. As with every halogenated organic compound, care should be taken in the extraction when using methylene chloride, a suspected carcinogen. Published: July 14, 2011 1437
dx.doi.org/10.1021/ed100522g | J. Chem. Educ. 2011, 88, 1437–1438
Journal of Chemical Education Scheme 1. The reaction of propionitrile and Fenton’s reagent forms two radicals (1 and 2) that can combine to form products 3 5
LABORATORY EXPERIMENT
and data interpretation in a safe reaction that can be easily completed in one laboratory session.
’ ASSOCIATED CONTENT
bS
Supporting Information A full experimental section with raw student data; mass spectrometry interpretation; instructor notes; and a worksheet for calculating the selectivity ratio. This material is available via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*E-mail: (R.P.H.)
[email protected]; (A.R.P.) allan.
[email protected].
’ RESULTS AND DISCUSSION Propionitrile (CH3CH2CN) can form two radicals: a resonancestabilized 2° radical (1) formed by abstraction of a hydrogen atom R to the nitrile or a 1° radical (2) by abstraction of a hydrogen atom β to the nitrile. The products formed by all possible combinations of these two radicals are illustrated in Scheme 1. All four isomers of the coupling product are easily observed and separated on the GC by at least 1 min. Stereoisomers of 2,3dimethylsuccinonitrile (4) (dl-pair and a meso compound) are generated in about a 1:1 ratio by the coupling of two molecules of the 2° radical (1). To determine the regiochemistry of hydrogen-atom abstraction, it is the sum of the peak areas of these two isomers that is important. Two 1° radicals (2) combine to form adiponitrile (5), whereas cross-coupling of radicals 1 and 2 produce 2-methylglutaronitrile (3). The average observed ratio for dinitrile isomers 3:4:5 is 50:31:19. Because there are three primary hydrogen atoms and only two secondary hydrogen atoms in propionitrile, a correction must be made. This is accomplished by dividing the amount of each radical formed by the number of abstractable hydrogens at each position. It was determined that the resonance-stabilized 2° radical (1) and the 1° radical (2) form in a 1.90:1 ratio rather than the statistical ratio of 2:3. These results are an average of 19 students over two years: spring semester 2009, 11 students, 1.86 ( 0.05; spring semester 2010, 8 students, 1.95 ( 0.24; combined, 19 students, 1.90 ( 0.16. (A worksheet for calculating the selectivity ratio may be found in the Supporting Information.) GC MS analysis reveals that isomers 3 and 5 have similar mass spectra (the spectra are shown in the Supporting Information). They can be distinguished by the known difference in boiling points and by the injection of an authentic sample of adiponitrile (5). The mass spectra of the dl-pair and meso stereoisomers of 4 are exactly the same, but are different from the spectra for isomers 3 and 5. For the regiochemical analysis, it is not necessary to know which peak corresponds to which stereoisomer of 4 because they are derived from the same secondary radical.
’ ACKNOWLEDGMENT The authors thank the Mount St. Joseph organic chemistry laboratory students (CHE 212A). ’ REFERENCES (1) See for example: (a) Brown, W. H.; Foote, C. S.; Iverson, B. L.; Anslyn, E. V. Organic Chemistry, 5th ed.; Brooks/Cole Cengage Learning: Belmont, CA, 2009. (b) Solomons, T. W. G.; Fryhle, C. B. Organic Chemistry, 10th ed.; John Wiley and Sons: Hoboken, NJ, 2011. (c) Smith, J. G. Organic Chemistry, 3rd ed.; McGraw Hill: New York, 2008. (2) Discovered by Fenton in 1894: Fenton, H. J. H. J. Chem. Soc. 1894, 899. (3) (a) Sawyer, D. T. J. Chem. Educ. 2005, 82, 985. (b) Sawyer, D. T.; Sobkowiak, A.; Matsushita, T. Acc. Chem. Res. 1996, 29, 409. (4) Walling, C. Acc. Chem. Res. 1998, 31, 155. (5) Luehrs, D. C.; Roher, A. E. J. Chem. Educ. 2007, 84, 1290. (6) Keller, C. L.; Dalessandro, J. D.; Hotz, R. P.; Pinhas, A. R. J. Org. Chem. 2008, 73, 3616.
’ NOTE ADDED IN PROOF The authors thank Prof. David Reingold of Juniata College for his interest and helpful suggestions. Using a GC equipped with a flame ionization detector, Reingold’s class obtained a ratio of the secondary to the primary radical of 2.07 to 1.
’ CONCLUSION An experiment has been developed in which the hydrogenatom abstraction from propionitrile is studied. In this experiment, students will learn about regiochemistry, stereochemistry, 1438
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