In the Laboratory
Competitive Nitration of Benzene–Fluorobenzene and Benzene–Toluene Mixtures: Orientation and Reactivity Studies Using HPLC
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Ronald L. Blankespoor,* Stephanie Hogendoorn, and Andrea Pearson Department of Chemistry and Biochemistry, Calvin College, Grand Rapids, MI 49546; *
[email protected] Given the importance of electrophilic aromatic substitution (EAS) in organic synthesis, it is not surprising that a number of EAS experiments have appeared in this Journal (1–6) and in laboratory manuals for first-year organic courses (7). Of particular interest has been the orientation (regiochemistry) and reactivity effects of substituents upon this process (1–3, 5, 8). For many years we determined the orientation of the methyl group in the nitration of toluene in one experiment and studied the reactivity effect of the methyl group in a second experiment by competitively brominating a benzene–toluene mixture. Gas chromatography was used to analyze the reaction mixtures from both experiments. When we designed a new EAS experiment for our organic sequence, we had several goals in mind. First, we wanted to study both the orientation and reactivity effects of a substituent in one experiment. Second, we wanted to use HPLC to analyze the reaction mixtures. Given the importance of HPLC as an analytical tool in industry and academia, we felt that this instrumental method was under-utilized in our curriculum. Finally, we wanted to give our students the option of determining the orientation and reactivity effects of an activating or deactivating substituent. Experiment The experiments we chose to accomplish these goals are the competitive nitration of benzene–toluene and benzene– fluorobenzene. The advantages of nitrating aromatic compounds are twofold: nitroaromatics are easily detected in HPLC instruments with UV–vis detectors and polynitration is not a problem at low temperatures. The CH3 group was chosen as one of the substituents because it activates the ring towards EAS and directs ortho–para. Although methyl is considered to be a weakly activating group, the relative reactivity of toluene to benzene towards nitration (i.e., kt兾kb) varies considerably depending upon the method of nitration and other conditions. For example, kt兾kb increases from 4.8 using HNO3–80% H2SO4 to 17 with HNO3–68% H2SO4 and it further increases to 23 when the nitration is done using HNO3–(CH3CO)2O (9). The second substituent we chose is fluorine, which deactivates the ring and is an ortho–para director. Fluorine is unique within the halogens in EAS reactions. As noted in McMurry’s textbook for first-year organic students (10), fluorobenzene is almost as reactive as benzene with the order of reactivity PhH > PhF > PhCl > PhBr > PhI. It is also unique within the halogen group in that it gives a much higher percentage of the para isomer than the other halogens. The anomalous reactivity of fluorobenzene in EAS has recently been addressed in this Journal (8) where the authors make the familiar argument that www.JCE.DivCHED.org
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the resonance effect of fluorine (i.e., π-electron donation) is much stronger than for the other halogens.1 Another reason for choosing the fluorine as a substituent is that we believe it is instructive for students to observe that the ortho–para ratio can greatly deviate from the statistically expected 2:1 value. Hazards We recommend the use of gloves and safety glasses throughout this experiment. All procedures, including the preparation of the sample for HPLC analysis, must be conducted in a fume hood. Care should be exercised in the handling of the following chemicals. Nitric acid and 10% NaOH are exceedingly corrosive liquids. Exposure may cause severe burns. Avoid skin contact. Acetic anhydride is a severe lachrymator. Avoid skin contact and inhalation. Benzene, fluorobenzene, and toluene are volatile organic liquids. Benzene is a carcinogen under chronic exposure conditions. Avoid skin contact and inhalation. Nitroaromatic compounds are respiratory hazards. Avoid inhalation. Results The HPLC of a reaction mixture obtained from the nitration (HNO3 in acetic anhydride) of a 3.6:1.0 mole ratio of benzene–toluene mixture after most of the excess reactants have been removed by evaporation is shown in Figure 1. A high ratio of benzene to toluene was used to generate an ap-
Figure 1. HPLC of reaction mixture from the nitration of benzene– toluene using a reverse-phase column with 60% methanol–40% water as solvent.
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In the Laboratory
preciable quantity of nitrobenzene for HPLC analysis. Doubling this ratio to 7.2:1.0 did not affect the relative reactivity of benzene and toluene appreciably. Using peak areas from standard solutions and adjusting for differences in molar absorptivities, the relative yields of the o-, m-, and p-nitrotoluenes are 55, 3.0, and 42%, respectively, clearly establishing the CH3 group as an ortho–para director. The slightly less than 2:1 ratio of o- and p-nitrotoluene can be attributed to a small steric effect of the methyl group. Further analysis of the chromatogram shows that the CH3 activates the aromatic ring by a factor of 49 (see the Supplemental MaterialW for details of the calculation). Some students are surprised by this large effect given that textbooks typically describe the methyl group as a weakly activating substituent. The HPLC in Figure 2 shows the mixture that is obtained from the nitration of 1.0:12 mole ratio of benzene– fluorobenzene after most of the excess reactants have been removed by evaporation. A high ratio of fluorobenzene to benzene was used to generate appreciable quantities of the nitrofluorobenzenes for HPLC analysis. Doubling this ratio to 1.0:24 did not affect the relative reactivity of fluorobenzene and benzene appreciably. Analysis of the chromatogram, as described above, allows students to conclude that the fluorine atom deactivates the aromatic ring by only a factor of 0.31, which is slightly higher than the value of 0.15 reported by Ingold et al. (11). The relative yields of the o-, m-, and pfluoronitrobenzenes (34:5.0:61, respectively) clearly establish the fluorine atom as an ortho–para director, but the ratio of the ortho:para isomers is considerably less than 2:1 showing a pronounced inductive, deactivating effect at the ortho position.
Figure 2. HPLC of reaction mixture from the nitration of benzene– fluorobenzene using a reverse-phase column with 50% acetonitrile– 50% water as solvent.
the students and notes for the instructor are available in this issue of JCE Online. Note 1. The orbitals in fluorine containing the lone pairs of electrons are close in distance and very similar in size to the empty p orbital on the adjacent carbocation. As a consequence, through more effective orbital overlap, fluorine is better at donating electron density to the carbocation than the other halogens.
Conclusion The nitration of the benzene–toluene and benzene–fluorobenzene mixtures nicely accomplishes our objective of studying the reactivity and orientation effects of a substituent in a single experiment. By having half of the organic class study the effects of the CH3 group and the other half work with F, we also achieve our goal of having our students see the effects of two different substituents. We have explored the use of other substituents, such as Cl, Br, I, CN, and CF3, but none of these give the relatively clean HPLCs that we obtain from the benzene–toluene and benzene–fluorobenzene reaction mixtures. Finally, it should be noted that HPLC is an excellent instrumental method to use in analyzing these mixtures. Using an HPLC equipped with an autosampler we generally analyze the samples overnight and give the chromatograms to the students the following day. W
Supplemental Material
HPLC equipment and conditions used in this experiment, analyses of the chromatographic data, instructions for
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Literature Cited 1. Zaczek, N. M.; Tyszkiewicz, R. B. J. Chem. Educ. 1986, 63, 510–511. 2. Ferguson, P. R. J. Chem. Educ. 1971, 48, 405–407. 3. Cox, B.; Kubler, D. G.; Wilson, C. A. J. Chem. Educ. 1977, 54, 379. 4. Beishline, R. R. J. Chem. Educ. 1972, 49, 128–129. 5. Gilow, H. J. Chem. Educ. 1977, 54, 450–452. 6. Jarret, R. M.; New, J.; Patraitis, C. J. Chem. Educ. 1995, 72, 457–459. 7. See, for example, Lehman, J. W. Microscale Operational Organic Chemistry: A Problem-Solving Approach to the Laboratory Course; Pearson/Prentice-Hall: Upper Saddle River, NJ, 2004. 8. Rosenthal, J.; Schuster, D. I. J. Chem. Educ. 2003, 80, 679– 690. 9. Olah, G. A. Acc. Chem. Res. 1971, 4, 240. 10. McMurry, J. Organic Chemistry, 4th ed.; Brooks/Cole Publishing Company: Albany, NY, 1996. 11. Gould, E. S. Mechanism and Structure in Organic Chemistry; Holt, Rinehart, and Winston: New York, 1959; p 428.
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