Using NMR Spectroscopy To Elucidate the Effect of Substituents on

Chapter 13

Using NMR Spectroscopy To Elucidate the Effect of Substituents on Keto-Enol Equilibria Downloaded by COLUMBIA UNIV on March 20, 2013 | http://pubs.acs.org Publication Date (Web): March 19, 2013 | doi: 10.1021/bk-2013-1128.ch013

Anderson L. Marsh* Department of Chemistry, Lebanon Valley College, 101 N. College Avenue, Annville, Pennsylvania 17003 *E-mail: [email protected]

In the physical chemistry laboratory, students are generally tasked with using quantitative results to explain trends in chemical reactivity. In one such experiment at Lebanon Valley College, students use proton nuclear magnetic resonance (1H NMR) spectroscopy to understand the effects of substituents on keto-enol tautomerization equilibria in a series of substituted β-diketones. The results illustrate to the students that additional effects beyond those that involve electron donation or electron withdrawal, such as resonance effects, need to be considered. Furthermore, the experiment allows students to use NMR spectroscopy as a quantitative tool rather than simply as a qualitative aid in structure characterization.

Introduction In the laboratory curriculum at Lebanon Valley College, undergraduate chemistry and biochemistry majors are introduced to nuclear magnetic resonance (NMR) spectroscopy in the spring semester of their first year, where it is used to characterize synthesized aspirin. Laboratories during the second year focus on structural characterization of more complex organic and inorganic compounds, which is especially useful for those students interested in working on a synthetic research project. It is not until the analytical and physical chemistry laboratory sequences that students are introduced to the quantitative aspects of NMR spectroscopy. © 2013 American Chemical Society In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

Downloaded by COLUMBIA UNIV on March 20, 2013 | http://pubs.acs.org Publication Date (Web): March 19, 2013 | doi: 10.1021/bk-2013-1128.ch013

A widely used experiment in the physical chemistry laboratory involves the determination of keto-enol equilibrium constants for various diketones (1–4). Students use 1H NMR spectroscopy to find the amount of each tautomer in a solution, since separate resonance signals are observed for protons in the keto and the enol species. Among the variables examined as affecting the equilibrium distribution are concentration (2, 3), solvent (2–4), and temperature (2, 3, 5). Kinetic variations have been described (5, 6), as well as chemical structure effects with a series of β-diketones and β-ketoesters (1, 2, 4). It is also noted that the substituents on the α-carbon of 2,4-pentanediones may affect the keto-enol equilibria (1). A reaction equilibrium involving a 3-substituted-2,4-pentanedione is shown in Scheme 1. In the initial version of this laboratory experiment developed at Lebanon Valley, students performed this experiment using the methyl and chloro substituted forms in addition to 2,4-pentanedione (7). The experiment has recently been updated to include the addition of several other 3-substituted-2,4-pentanediones, along with another quantitative aspect that involves substituent constants.

Scheme 1. The tautomeric equilibrium of a 2,4-pentanedione derivative with a substituent on the α-carbon

Experimental Methods Deuterated chloroform containing tetramethylsilane (TMS), 2,4-pentanedione, 3-chloro-2,4-pentanedione, 3-methyl-2,4-pentanedione, 3-ethyl-2,4-pentanedione, and 3-acetyl-2,4-pentanedione, also known as triacetylmethane, were purchased from Sigma-Aldrich and used without further purification. The diketones 3-butyl-2,4-pentanedione and 3-phenyl-2,4-pentanedione were obtained from TCI America and used without further purification. The diketone 3-phenylazo-2,4-pentanedione was obtained from Alfa Aesar and used without further purification. Students were given a handout referencing background information and published methods necessary to plan their own procedures to carry out the experiment. Prior to the laboratory period students were expected to locate and read the references. At the beginning of the experiment, students calculated volumes or masses needed to prepare solutions at a mole fraction of 0.001 of each 3-substituted-2,4-pentanedione in deuterated chloroform in standard NMR tubes and wrote out a detailed procedure in their laboratory notebooks. Students then worked in groups of two to four individuals to prepare their solutions. After these were prepared, student groups acquired standard 1H NMR spectra using a Bruker 206 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

Avance 300 MHz FT-NMR spectrometer. The program uses a 30° excitation pulse, a 4.4 s acquisition time, and a 2 s relaxation delay over 16 scans (6). The temperature of the probe is maintained at 297 K. Because the cost of several of the diketones is prohibitive to using amounts that yield a 0.2 mole fraction in solution, a mole fraction of 0.001 was used. A prior report demonstrated that 2,4-pentanedione solutions of this mole fraction yielded similar results for equilibrium constants found when using solutions of 0.2 mole fraction (4). For the hydrogen, methyl, and chloro substituents, no significant variation from our previously published results was observed (6).


Results and Discussion Results from student NMR data are summarized in Table 1. Chemical shifts are reported relative to tetramethylsilane (TMS).

Table 1. NMR shift assignments, peak integrations, and experimentally determined values of the keto-enol equilibrium constant Kc from student data keto CH3

enol CH3

shift (ppm)

int

shift (ppm)

int

Kc

2,4-pentanedione

2.2

1.39

2.1

6.71

4.83

3-methyl-2,4-pentanedione

2.2

8.93

2.1

6.70

0.750

3-ethyl-2,4-pentanedione

2.2

15.83

2.1

7.36

0.465

3-butyl-2,4-pentanedione

2.3

11.36

2.2

6.21

0.550

3-chloro-2,4-pentanedione

2.4

0.48

2.3

6.07

13

3-acetyl-2,4-pentanedione

2.3

1.12

2.3

6.12

5.46

3-phenyl-2,4-pentanedione

--

--

1.8

5.87

--

compound

Student groups assigned the chemical shifts in their spectra using integrated peak intensities, as well as results found in the literature (8–12). The spectra for the pentanediones with the hydrogen, methyl, ethyl, butyl, chloro substituents on the α-carbon presented no problems for the student groups to analyze. Because the enol species is the sole tautomer existing in solution for the pentanedione with the phenyl substituent, the spectrum was easier for the student groups to assign than if a mixture of tautomers existed. The spectrum for the pentanedione with the acetyl substituent was the most challenging for the student groups to evaluate, particularly since the peak for the protons on the three methyl groups in the keto form overlaps with the peak for two of the methyl groups on the enol form (11). Equilibrium constants were calculated by the student groups from peak integrations for the protons in the keto and enol methyl groups bonded to the carbonyls using 207 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.


where [enol] and [keto] represent the corresponding peak integrations. As seen from the data in the table, the equilibria for the pentanediones with the alkyl substituents (methyl, ethyl, and butyl) favor the keto tautomer, whereas the equilibria for the pentanediones with the hydrogen, chloro, and acetyl substituents favor the enol tautomer. For the pentanedione with the phenyl substituent, the equilibrium lies completely with the enol tautomer. Once again, these observations made by the student groups are supported by previous literature results (8–11). In explaining the findings, the student groups initially argued that electron donating or electron withdrawing effects were responsible. For example, one would expect the alkyl substituents to be electron donating, which should lead to stabilization of the keto form (13). As mentioned above, this result is in fact what the student groups observed. On the other hand, electron withdrawing substituents, such as chloro or acetyl, should result in the enol being favored, as observed by the student groups. In order to quantify this inductive argument, the student groups compared equilibrium constants to Hammett substituent constants, the results of which are summarized in Table 2.

Table 2. Comparison of keto-enol equilibrium constants Kc with Hammett substituent constants Kc

σpara

2,4-pentanedione

4.83

0.00

3-methyl-2,4-pentanedione

0.750

–0.14

3-ethyl-2,4-pentanedione

0.465

–0.15

3-butyl-2,4-pentanedione

0.550

–0.16

3-chloro-2,4-pentanedione

13

0.47

3-acetyl-2,4-pentanedione

5.46

0.24

3-phenyl-2,4-pentanedione

--

–0.01

compound

The student groups researched Hammett constants in the literature and decided that the para substituent constants would be the most suitable for comparison (14). As observed with the data in the table, there is some correlation between the magnitude of the para substituent constant and the magnitude of the keto-enol equilibrium constant. Only in the case of the phenyl substituent is there no agreement. Still, Hammett plots of log Kc versus σpara constructed by the student groups showed less than ideal correlation coefficients from the linear regression analysis. On the other hand, resonance forms could yield a 208 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

greater stabilization of the enol tautomer. This resonance induced stabilization would explain the predominance of the enol form for the phenyl substituted pentanedione, as well as the chloro substituted pentanedione, especially if one considers contributions from the d orbitals on the chlorine atom (10).


Conclusions Using NMR spectroscopy as a quantitative tool has allowed students in the Physical Chemistry laboratory course at Lebanon Valley College to examine structure-reactivity relationships for equilibria involving keto and enol tautomers in solution. Each student group designs and plans experimental procedures, collects data, and analyzes their findings. The experiment allows them to think about qualitative concepts learned during organic chemistry in a more quantitative manner that is traditional to physical chemistry. While interpretation of the NMR spectra may be challenging to some of the student groups, the solutions may be prepared and the spectra may be collected easily during a normal four hour laboratory period. The laboratory experiment has recently been revised even further to a guided inquiry version where students are required to predict a trend in the equilibrium constants prior to performing the experiment in the laboratory. Interestingly, the student groups this time again invoked an electron donating/withdrawing argument in developing a hypothesis. Further updates may include having the students use the Taft substituent constants, which account for both polar and steric effects, as a means of quantifying their observations with regards to the equilibrium constants (15). In addition, student groups could perform the experiments using solvents of different polarities and pool their data before deriving conclusions. A computational component could also be introduced in order to more fully understand the effect of resonance structures. Finally, independent projects performed by students in the course could involve the synthesis of a substituted pentanedione for which the equilibrium constant has not been determined.

References 1.

2. 3. 4. 5. 6. 7.

Garland, C. W.; Nibler, J. W.; Shoemaker, D. P. Experiment 42: NMR Determination of Keto-Enol Equilibrium Constants. In Experiments in Physical Chemistry, 8th ed.; McGraw-Hill: New York, 2009; pp 466−474. Drexler, E. J.; Field, K. W. J. Chem. Educ. 1976, 53, 392–393. Grushow, A.; Zielinski, T. J. J. Chem. Educ. 2002, 79, 707–714. (a) Cook, A. G.; Feltman, P. M.; J. Chem. Educ. 2007, 84, 1827−1829. (b) Cook, A. G.; Feltman, P. M.; J. Chem. Educ. 2010, 87, 678−679. Koudriavtsev, A. B.; Linert, W. J. Chem. Educ. 2009, 86, 1234–1237. Nichols, M. A.; Waner, M. J. J. Chem. Educ. 2010, 87, 952–955. (a) Manbeck, K. A.; Boaz, N. C.; Bair, N. C.; Sanders, A. M. S.; Marsh, A. L. J. Chem. Educ. 2011, 88, 1444−1445. (b) Manbeck, K. A.; Boaz, N. C.; Bair, N. C.; Sanders, A. M. S.; Marsh, A. L. J. Chem. Educ. 2012, 89, 421. 209 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

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210 In NMR Spectroscopy in the Undergraduate Curriculum; Soulsby, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2013.

Using NMR Spectroscopy To Elucidate the Effect of Substituents on

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