In the Laboratory
Molecular Mechanics and Variable-Temperature 1H NMR Studies on N,N-Diethyl-m-toluamide An Undergraduate NMR and Molecular Modeling Experiment Bruce L. Jensen* and Raymond C. Fort Jr. Department of Chemistry, University of Maine, Orono, ME 04469; *
[email protected] One of the most popular and widely used undergraduate organic chemistry laboratory experiments is the preparation of the insect repellent N,N-diethyl-m-toluamide (DEET). CH2CH3 O
N
CH2CH3
CH3
N,N - Diethyl -m - toluamide
This experiment is found in many microscale (1) and macroscale (2) laboratory textbooks and represents an excellent demonstration of nucleophilic acyl substitution. The original experiment has been improved by using bis(trichloromethyl)carbonate in place of thionyl chloride and flash chromatography in place of column chromatography (3). These changes allow for a microscale synthesis rather than the multigram scale previously employed. In addition to an interesting synthesis, the experiment described herein makes novel use of 1H NMR spectroscopy, an integral part of most sophomore courses (4), and introduces students to some basic ideas of molecular modeling. In the
538
view of most practitioners, molecular modeling in its various forms is now accessible enough to be considered just another spectroscopy. This is particularly true of molecular mechanics, the principles of which are well within the reach of second- and third-year students. “Molecular modeling allows the student to think more clearly about issues which are fundamental to the study of organic chemistry … structure, stability, and reactivity … than would be possible without the use of a computer” (5). Furthermore, the exercise described herein can be done as a team experiment—one student to synthesize, one to do the spectroscopy, and one to do the modeling—thus connecting the students with the real way in which scientific work is done. Experiment All variable-temperature 1H NMR spectra were recorded on a Varian Gemini 300 MHz instrument as 0.14 M solutions of DEET in deuterochloroform with tetramethylsilane as an internal standard. Standard NMR tubes (5-mm o.d.) with pressure-release caps were found to work satisfactorily over the temperature range (9–85 °C) used in this experiment. Temperatures were calibrated against an ethylene glycol standardized curve.
Journal of Chemical Education • Vol. 78 No. 4 April 2001 • JChemEd.chem.wisc.edu
In the Laboratory
Hazards
33
There are no significant hazards associated with this experiment.
31
27
25
23
21
19 0
50
100
150
200
250
300
350
300
350
Dihedral Angle / deg Figure 1. Amide rotation, no delocalization. 30
25
E / (kcal/mol)
In our laboratory program, we have integrated molecular modeling and molecular mechanics calculations with a variabletemperature 1H NMR spectrometry study of the barrier to rotation around the amide bond. This experimental project combines the power of 1H NMR spectrometry to analyze molecular phenomena with the ability of computers to calculate the potential energy of a set of conformations obtained by a 360° dihedral drive around the N–CO bond. Students are introduced to the basics of molecular modeling, including constructing the computer model of DEET using PCMODEL, minimizing the structure, establishing the atoms for a dihedral drive, and conducting the drive (6 ). A second dihedral drive that incorporates a π calculation is then done by designating the amide linkage as a set of π atoms that can interact by resonance. A comparison of the two dihedral maps shows high and low energy conformations with energy differences ranging from 12.0-15.9 kcal/mol and a π contribution of 3.9 kcal/mol (see Figs. 1 and 2). The students are then asked to evaluate the 1H NMR spectrum of DEET that they obtained from their laboratory preparation. In all cases, the spectral regions displaying the aromatic methyl group and aromatic hydrogens will be sharp and well resolved. However, depending upon the type of NMR system used (7), the ethyl group absorptions will be vastly different. When the NMR analysis is performed on a superconducting spectrometer with a probe temperature of 18 °C (see Fig. 3), the methylene protons are displayed as two broad absorptions at 3.2–3.6δ and two broad methyl absorptions at 1.1–1.3δ . On the other hand, the NMR spectrum obtained from a continuous-wave instrument (8) using a 60-MHz permanent magnet operating at 35 °C will show a broad methylene group absorption at 3.6δ and a sharp methyl group triplet centered at 1.1δ. Students are then asked to predict how the 1H NMR absorptions for the ethyl groups might change if the rate of rotation around the amide bond is either very fast or stopped altogether. Plastic models can be used for illustration. Students will have to be reminded that the NMR experiment is very slow in comparison to the time-frame of a typical C–C bond rotation and that alkanes generally have a low energy barrier to rotation (3–5 kcal/mol). For example, the internal rotation found in butane occurs approximately 1011 times per second. On the other hand, a typical amide bond with an energy barrier for rotation of 17 kcal/mol results in an internal rotation rate of about 10 times per second (9). With these concepts in mind, the variable-temperature NMR spectra for DEET are shown to the students. At 18 °C, the ethyl groups are displayed as two sets of broad absorptions at 3.2–3.6δ and 1.1–1.3δ. The presence of two absorptions each for the methylene and methyl groups is consistent with two nonequivalent ethyl groups, yet bond rotation is also fast enough for time averaging to cause broadening of all four absorptions. At 35 °C, the increased rate of rotation has caused a coalescence of the methyl signals and the beginning of the merger of the methylene signals. At 44 °C,
E / (kcal/mol)
29
Results and Discussion
20
15
10 0
50
100
150
200
250
Dihedral Angle / deg Figure 2. Amide rotation, including delocalization.
Figure 3. Stacked NMR spectral array.
the methylene signal is very broad but the methyl signal has sharpened dramatically. At 55 °C the methyl triplet is beginning to emerge while the methylene absorption remains unresolved. At 85 °C, a fully resolved triplet centered at 1.17δ is observed along with a slightly broadened quartet at 3.4δ. Thus at 85 °C the rotation around the amide bond is so fast that the NMR “sees” a time-averaged ethyl group.
JChemEd.chem.wisc.edu • Vol. 78 No. 4 April 2001 • Journal of Chemical Education
539
In the Laboratory
As can be seen in Figure 3, a change of only 10° below room temperature results in insufficient thermal energy to surmount the energy barrier of 15.9 kcal/mol. As a result, the low energy conformation displays two nonequivalent ethyl groups, each possessing a quartet and triplet. The PCMODEL structure of this conformation clearly shows that the carbonyl group is orthogonal to the aromatic ring, leaving the N-ethyl groups projected into totally different regions in space on the opposite side of the ring (Fig. 4). The energy barrier calculated by this means is in complete agreement with the values calculated by Siddall and coworkers using signal-shape analysis (10). Acknowledgments We thank the National Science Foundation, ILI grants DUE-9352266 and DUE-9551313, for the purchase of the 300-MHz Varian Gemini spectrometer and the molecular modeling computers and software used in this experiment. Literature Cited 1. Pavia, D. L.; Lampman, G. M.; Kriz, G. S.; Engel, R. G. Organic Laboratory Techniques. Small-Scale Approach; Saunders: Philadelphia, 1998; pp 145–151. 2. Mohrig, J. R.; Hammond, C. N.; Morrill, T. C.; Neckers, D. C. Experimental Organic Chemistry; Freeman: New York, 1998; pp 313–326. 3. LeFevre, J. W. J. Chem. Educ. 1990, 67, 278. 4. Alexander, C. W.; Asleson, G. L.; Doig, M. T.; Heldrich, F. J. J. Chem. Educ. 1999, 76, 1294–1296.
540
Figure 4. Low-energy conformation of DEET.
5. Kantardjieff, K. A.; Hardinger, S. A.; Van Willis, W. J. Chem. Educ. 1999, 76, 694–697. 6. PCMODEL V 7.0; Serena Software: Bloomington, IN 47402. 7. Silverstein, R. M.; Webster, F. X. Spectrometric Identification of Organic Compounds, 6th ed.; Wiley: New York, 1998; pp 144–199. 8. Pouchert, C. J. Aldrich Library of NMR Spectra, Vol. VII, 2nd ed.; Aldrich Chemical Co.: Milwaukee, WI, 1983; p 74 (D10,095-1). 9. Loudon, G. M. Organic Chemistry, 3rd ed.; Benjamin/ Cummings: Redwood City, CA, 1995; p 979. 10. Siddall, T. H.; Stewart, W. E.; Knight, F. D. J. Phys. Chem. 1970, 74, 3580.
Journal of Chemical Education • Vol. 78 No. 4 April 2001 • JChemEd.chem.wisc.edu
