A More Challenging Interpretative Nitration Experiment Employing

In the Laboratory

A More Challenging Interpretative Nitration Experiment Employing Substituted Benzoic Acids and Acetanilides Edward M. Treadwell* and Tung-Yin Lin Department of Chemistry, Eastern Illinois University, Charleston, IL 61920; *[email protected]

Electrophilic aromatic substitution is a key topic in organic chemistry, illustrating the fundamental concepts of inductive and resonance effects in terms of relative reactivity and regiose� lectivity. Several excellent experiments on this topic have been developed, involving analysis of a single product by melting point and spectral characterization (1), determining product ratios by GC or GC–MS analysis (2), �� or�� gauging relative reactiv� ity in competition experiments (3). We sought to add another experiment to this repertoire in which disubstituted aromatic starting materials were used, and the products analyzed solely by NMR. The experiment also introduced spectral interpretation of mixtures (something that we do not commonly assay but is commonly encountered in real life) and a molecular modeling facet to solve chemical problems (4). Thus our experiment would have the students

• predict the regioselectivity of a nitration reaction with a disubstituted benzene

• employ computational methods to evaluate the regio selectivity of the nitration reaction

• determine the regioselectivity and product distribution of the product(s) solely by 1H NMR spectroscopy

• integrate all three areas in their written report

Experimental Overview On day one, the students added a freshly prepared (in hood, in an ice bath) nitrating solution of concentrated nitric and sulfuric acids to a cold, stirred solution of 0.045 mol1 of their aromatic compound in sulfuric acid over 20 min. The students then poured their reaction mixture into a beaker of ice, and collected the product by vacuum filtration. Recrystallization afforded a product suitable for analysis. On day two, the students collected the 1H NMR spectrum in acetone-d6 on a 400 MHz Bruker Avance spectrometer and used the TOPSPIN software on the instrument to work up the data. �� Additionally�� , the stu� dents performed molecular modeling calculations using Spartan 04 with the AM1 basis set to determine the heats of formation of the four possible cationic intermediates. Since the compounds have several different starting orientations (for instance, the dihedral angle for the OC=O−CC=O−C−Cx could be either 0 or 180°), a conformational search preceded the geometry cal� culations to provide more meaningful comparative results. The students then presented their data, analysis, and comparison of experimental techniques in a written report. Hazards Concentrated nitric and sulfuric acids are very caustic and can cause extreme burns, so the flasks should be corked at all times to avoid inhalation or vapor burns. The nitrating mixture should be prepared in a hood as it is exothermic, and gloves should be worn throughout the experiment. Toluene and

ethanol are flammable solvents, and the former is a poison and irritant and should be used only in a hood. Results and Conclusions Products Representative student results after recrystallizations are shown in Table 1, and in all cases students obtained sufficient product for analysis. The reaction tolerated quicker additions of the nitrating agent, except for the more reactive o-methoxy� benzoic and o-hydroxybenzoic acids. While yields and product ratios for individual students varied significantly (as did their ability to perform recrystallizations successfully), the overall trends were conserved in all cases. For the ortho-substituted acids, the products consisted of the 5-nitro product with smaller quantities of 3-nitro product present, except that o-fluorobenzoic acid gave only the 5-nitro product. The meta haloacids gave solely the 6-nitro product with varying quantities of unreacted starting material present. Mixtures of 5-nitro and 4-nitro products were found with ortho-chloroacetanilide, while meta-chloroacetanilide afforded mixtures of 4-nitro and 6-nitro products. These results can be rationalized considering the directing abilities of the two sub� stituents. With the ortho-substituted acids, the two reinforcing substituents direct to the C3 and C5 positions. Reinforcing directing groups are also present with meta-chloroacetanilide, to give nitration at C4 and C6. With the meta-substituted acids the ortho- and para-activating halogens dominated over the meta-deactivating carboxyl group to give nitration at C6. With ortho-chloroacetanilide, the nearly 1:1 regioselectivity demonstrated that with the conflicting ortho and para directors were approximately equal in their directing ability.

Table 1. Selected Student Results of Nitrations After Recrystallization Starting Material

Yield (%)

Product Ratio

o-Fluorobenzoic acid

92

only 5-nitro

o-Chlorobenzoic acid

64

6.0:1.0 5-nitro:3-nitro

o-Bromobenzoic acid

78


o-Methylbenzoic acid

56


o-Methoxybenzoic acid

83


o-Hydroxybenzoic acid

40


m-Fluorobenzoic acid

81

only 6-nitro

m-Chlorobenzoic acid

45

4.1:1.0 6-nitro:st mat

m-Bromobenzoic acid

60

only 6-nitro

o-Chloroacetanilide

50


m-Chloroacetanilide

51


Note: st mat is starting material.

© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 85 No. 11 November 2008 • Journal of Chemical Education

1541

In the Laboratory Table 2. Heats of Formation Calculated for Cationic Intermediates in the Nitration Reactions Δ f H/(kcal/mol)

Starting Material

2-nitro

3-nitro

4-nitro

5-nitro

6-nitro

o-Fluorobenzoic acid

—

111.174

121.920

108.767

121.664

m-Fluorobenzoic acid

124.558

—

112.707

116.528

110.370

o-Chloroacetanilide

—

196.355

170.948

196.222

178.849

m-Chloroacetanilide

206.066

—

175.165

201.569

169.414

Note: Energies are calculated using AM1 semiempirical methods with Spartan 2004. The lowest energy intermediate is bolded, while the next lowest energy intermediate is italized.

NMR It took the students approximately 15 minutes to collect and print out the 1H NMR spectra�� , which�� had enough suf� ficiently resolved signals for clear interpretation (Figure 1 and Table 3 in the online material). With the fluorobenzoic acids, H−F couplings gave more complex spectra. For the ortho- and meta-halobenzoic acids, the exact regiochemistry of the product could be determined when the directing groups present or the shift were considered. For example, the splitting pattern for one product from o-chlorobenzoic acid indicated a 1,2,4-trisubsti� tuted aromatic, which would be 2-chloro-5-nitrobenzoic acid rather than 2-chloro-4-nitrobenzoic acid as C5 is directed to by both groups while neither group directs to C4. Likewise, the splitting pattern for the product from m-chlorobenzoic acid indicated a 1,2,4-trisubstituted aromatic, but the 7 Hz doublet appearing downfield of the doublet of doublets suggested 5-chlo� ro-2-nitrobenzoic acid rather than 3-chloro-4-nitrobenzoic acid,

0.97

8.8

8.6

0.99

8.4

8.2

1.01

0.56 0.55

8.0

7.8

0.59

7.6

Chemical Shift (ppm) Figure 1. 400 MHz 1H NMR spectrum for the nitration of o-methyl benzoic acid.

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owing to the powerful electron-withdrawing nature of the nitro group. With the chloroacetanilides, spectral analysis indicated two 1,2,4-trisubstituted aromatic compounds were present, and identification of the regioisomers can be made by examining the relative ordering of the two doublet signals. In our curriculum, the students have already had significant exposure to 1H NMR spectral analysis in both the lecture and laboratory courses, and examples of spectral interpretation were given in the prelab lecture and in handouts to help guide the students. The students were instructed to first predict the splitting patterns for all four possible isomeric products and then to�� start �� the analysis by grouping the signals in their spec� trum by integral values. Some students were not comfortable with analysis based solely on coupling constants and initially focused on interpreting the shifts rather than the splitting pat� tern. Additionally, some students occasionally tried interpreting signals from two different regioisomers as belonging to the same compound. Assistance from the instructor during office hours helped students �� to �� overc�� o�� me the�� se�� misconceptions. Most stu� dents required at least a little assistance to lead them to assemble their interpretation of individual peaks into an overall structure. The most difficult spectra for the students to interpret were for o-bromobenzoic acid and acetanilides owing to the 1:1 ratios of products observed. Overall, the students started to appreciate using the integrals and splitting patterns to figure out the content of mixtures and after this laboratory exercise, could do so independently on quizzes or other assignments. Molecular Modeling The molecular modeling portion of the experiment went smoothly, especially if use of the software was demonstrated in the pre-laboratory discussion (see the online material). We emphasized that although the activation energies should be the values compared for a reaction under kinetic control, the heats of formations �� were�� calculat�� ed�� owing to computational simplic� ity. It took the students about 15–30 minutes to complete all four calculations, and the computational results were sufficiently disparate for trends to be observed (Table 2). The energy differ� ences between the intermediates became pronouncedly smaller for the meta-halobenzoic acid series, as would be expected when conflicting directing groups were present and the halogen becomes less activating. The only unexpected results were found for m-bromobenzoic acid, where the C5 nitrated material had a lower Δf H than the C6 nitrated material and o-chloroaceta� nilide, where the C6 isomer was lower in energy than the C5 isomer (see the expanded Table 2 in the online material). Use of ab initio calculations (HF 6-31G**) gave the predicted results,

Journal of Chemical Education • Vol. 85 No. 11 November 2008 • www.JCE.DivCHED.org • © Division of Chemical Education

In the Laboratory

though at a heavy computational time cost. We used this result to stress that computational results should always be viewed with a critical eye. With regard to the written lab reports, most students correctly identified the product(s) obtained and noted the cor� relation of predicted results to their results. In the laboratory and lecture classes following this experiment, we saw significant improvements in the students’ ability to correctly predict the regiochemistry of an electrophilic aromatic substitution on disubstituted aromatics, as well as interpret 1H NMR spectra of moderately complicated splitting patterns and mixtures. The students considered this to be a challenging lab, but enjoyed the “unknown” aspect in determining the product as well as the computational portion. In the end-of-course assessment a significant number of students stated that this experiment was the one they learned the most from. Acknowledgments We would like to thank Kraig A. Wheeler and Daniel J. Sheeran for suggestions and the National Science Foundation (MRI/RUI #0321321) for purchase of the 400 MHz spectrom� eter used herein. Note

(b) Pavia, D. L.; Lampman, G. M.; Kriz, G. S.; Engel, R. G. Introduction to Organic Laboratory Techniques: A Small-Scale Approach; Harcourt College Publishers: Fort Worth, TX, 1998; pp 297–300. (c) Varma, P. S.; Kulkarni, D. A. J. Am. Chem. Soc. 1925, 47, 143–147. Brominations: (d) Schatz, P. F. J. Chem. Educ. 1996, 73, 267. (e) Mohrig, J. R.; Hammond, C. N.; Morrill, T. C. Experimental Organic Chemistry: A Balanced Approach, Macroscale and Miniscale; W. H. Freeman and Co.: New York, 1999; pp 184–186. Friedel-Crafts acylations: (f ) Schatz, P. F. J. Chem. Educ. 1979, 56, 480. (g) Cox, B.; Kubler, D. G.; Wilson, C. A. J. Chem. Educ. 1977, 54, 379. 2. (a) Gilow, H. J. Chem. Educ. 1977, 54, 450–452. (b) Smith, Ross E., IV.; McKee, J. R.; Zanger, M. J. Chem. Educ. 2002, 79, 227–229. 3. (a) Zaezek, N. M.; Tyszkiewicz, R. B. J. Chem. Educ. 1986, 63, 510–511. (b) Clark, M. A.; Duns, G.; Golberg, D.; Karwowska, A.; Turgeon, A.; Turley, J. J. Chem. Educ. 1990, 67, 802. (�� c�� ) Kes� �� ler, B. S.; Williams, S. E. Chem. Educator 2000, 5, 223–225. (d) Schoffstall, A. M.; Gaddis, B. A.; Druelinger, M. L. Microscale and Miniscale Organic Chemistry Laboratory Experiments; McGrawHill: Boston, 2000; pp 289–294. (e) Gilbert, J. C.; Martin, S. F. Experimental Organic Chemistry, a Miniscale and Microscale Approach, 3rd ed.; Harcourt College Publishers: Fort Worth, TX, 2002; pp 483–490. 4. Andersh, B. Chem. Educator 2000, 5, 20–23.

1. In fact, the experiment could be performed on smaller quantities—0.022 or even 0.01 mole of starting material—and students would still have sufficient quantities of product.

Supporting JCE Online Material

Literature Cited

Full text (PDF) with links to cited JCE articles

1. Nitrations: (a) Gilbert, J. C.; Martin, S. F. Experimental Organic Chemistry, a Miniscale and Microscale Approach, 3rd ed; Har� court College Publishers: Fort Worth, TX, 2002; pp 473–483.

http://www.jce.divched.org/Journal/Issues/2008/Nov/abs1541.html Abstract and keywords Supplement

Student handouts

Instructor notes including 1H NMR spectral data

© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 85 No. 11 November 2008 • Journal of Chemical Education

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A More Challenging Interpretative Nitration Experiment Employing

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