In the Classroom
Application of ChemDraw NMR Tool: Correlation of Program-Generated 13C Chemical Shifts and pKa Values of para-Substituted Benzoic Acids Hongyi Wang Department of Chemistry, University of Florida, Gainesville, FL 32611 VisiGen Biotechnologies, Inc., 2575 West Bellfort, Suite 250, Houston TX 77054;
[email protected] Nuclear magnetic resonance spectroscopy (NMR) is a powerful tool to solve the structures of organic compounds. ChemDraw by Cambridgesoft offers a new feature to predict 13C and 1H NMR chemical shifts of organic compounds (1) that has been welcomed by the chemistry community. ChemDraw identifies a molecule’s key substructure that provides the base value for the estimated shift. The software views the remaining parts of the molecule as substituents of the substructure. Each substituent adds to or subtracts from the base shift of the substructure to which it is attached. Additivity rules determine the increment of each contribution. The data set for 1H NMR shift tool currently contains 700 base values and about 2000 increments. The 13C NMR tool is based on 4000 parameters. Linear correlation between the logarithms of rate constants and pKa values of substituted benzoic acids was independently discovered by Hammett and Burhardt in the 1930s and has been used extensively as a means of estimating the relative polarity of substituents (2). The Hammett σ value for the substituent is a reflection of the electronic effect of that substituent on the dissociation constant of the substituted benzoic acid. Similar correlation research has been performed among physical properties (NMR, UV, IR, electronic potentials, etc.) and chemical reactivity of organic compounds to gain a better understanding and prediction of the reactivity (3). Today an appreciation of the relationship between structure and reactivity is central to modern organic chemistry. Consequently, organic chemists can usually predict whether replacement of hydrogen by another group in a compound will be rate-increasing or rate-decreasing in a particular reaction or will be in favor or disfavor of certain equilibria processes. The author was inspired to combine the two aspects together to generate teaching materials for first-year organic chemistry students. Fifteen para-substituted benzoic acids (Scheme I) were chosen for several reasons: first, this system has historic importance as mentioned above; second, the substituents represent a wide range of organic functional groups
X
3 4
X 2 1
ⴙ Hⴙ 5
CO2
CO2H
ⴚ
X ⴝ NHMe, NMe2, NH2, OMe, OH, F, Me, Et, i-Pr, Cl, Br, H, CN, CO2H, NO2
Scheme I. Substituted benzoic acids.
1340
Journal of Chemical Education
•
with electron-withdrawing or electron-donating properties; third, only para-substitution was treated for simplicity. These compounds were processed with the ChemDraw NMR tool to generate 13C NMR chemical shifts of C1 through C5 (Scheme I). The data were then plotted against their pKa values (4) in Microsoft Excel and a fairly good linear fit was found for pKa versus δC1 with R 2 = 0.9412 (Table 1 and Figure 1). Correlations with chemical shifts of other carbons did not give useful results. As seen above, in a series of structurally related compounds 13C NMR chemical shift values could represent the electronic nature of a certain carbon, further, representing the polarity of substituents (5). It can be seen that C1 in this case is most sensitive to substituent effect. Analysis of experimental 13C NMR chemical shifts in the same manner as above would provide a good evaluation of the ChemDraw NMR tool as well as validation of this application. A literature search (6) gave a set of 13C NMR data of six para-substituted benzoic acids determined in DMSO-d6兾H2O (4兾1, pH < 1) as listed in Table 1. SDBS database (7) search gave another set of 13C NMR data of eight para-substituted benzoic acids determined in DMSO-d6 as listed in Table 1 (Several others were determined in CDCl3 and were not used here since NMR chemical shifts may be affected by solvents). These two sets of data were plotted the same way as above (Figure 1), giving R 2 = 0.8455 and R 2 = 0.9657, respectively. The DMSO-d6 data set and ChemDraw data set appear to give comparable linear fits. This may be due to the fact that ChemDraw NMR tool is mostly based on organic solvents. Although the pKa values were obtained in aqueous solution, these two sets gave good linear fits. It is interesting to note that NMR data from DMSO兾H2O and aqueous-based pKa values gave a relatively poor linear fit, which reflects the complexity of the molecular basis for the observed substitution effects in the aqueous acidities of benzoic acids. The chemical basis behind this correlation is at the very heart of organic chemistry: structure–reactivity relationship. Deprotonation of benzoic acid gives the conjugate base, benzoate anion, which carries a negative charge (Scheme I). In this equilibrium the para-substituents on the phenyl ring play an important role by stabilizing or destabilizing the benzoate anions regarding the developed negative charge. An electronwithdrawing group stabilizes the anion by sharing partial negative charge, thus giving a lower pKa value for a “stronger” acid. An electron-donating group, on the other hand, destabilizes the anion by further enriching electron density, thus giving a higher pKa value for a “weaker” acid. Transmitting a polar effect through the aromatic nucleus can involve both inductive and resonance paths.
Vol. 82 No. 9 September 2005
•
www.JCE.DivCHED.org
In the Classroom Table 1. Substituents, pKa Values, and 13C NMR Chemical Shifts in para-Substituted Benzoic Acids
pKa ⴝ −0.0729δC1 ⴙ 13.48 R 2 ⴝ 0.8455
Chemical Shift (ppm) Substituent
pKa
ChemDraw NMR tool
Experimentala DMSO-d6 116.7
Experimentalb DMSO-d6/ H2O
5.1
NHMe
5.04
119.0
NMe2
5.03
120.1
NH2
4.92
120.6
OMe
4.47
122.9
123.2
OH
4.58
123.2
121.4
F
4.14
126.2
127.4
126.8
3.9
Me
4.34
127.6
128.1
127.6
3.7
Et
4.35
127.8
i-Pr
4.35
127.8
Cl
3.99
128.7
129.7 130.0
Br
4.00
129.6
H
4.17
130.6
CN
3.55
134.9
CO2H
3.51
135.8
NO2
3.44
136.7
a
Data from ref 7.
pKa ⴝ −0.0771δC1 ⴙ 14.007 R 2 ⴝ 0.9657
4.9 4.7
pKa ⴝ −0.0891δC1 ⴙ 15.61 R 2 ⴝ 0.9412
122.4
pKa
4.5 4.3 4.1
3.5 3.3
129.2
130.5
136.5
116
118
120
122
124
126
128
130
132
134
136
138
δC1 (ppm) Figure 1. Correlation of pKa values and δC1 of para-substituted benzoic acids: (x, ....) experimental DMSO-d6/H20, (䊊, – – –) experimental DMSO-d6, (ⵧ, –––) ChemDraw NMR tool.
136.1
b
Data from ref 6.
In this project the author has tried to bring together organic chemistry concepts and techniques. It covers the following important concepts: Hammett equation, acid–base equilibrium theory, electronic nature of functional groups, inductive and resonance effects, structure–reactivity relationship, and NMR spectroscopy. It may also be used to introduce some basic research techniques: literature searches, database searches, and ChemDraw software usage. The project can be used as an assignment at the end of first-year organic chemistry class to review topics and explore new techniques. First, students learn how to draw chemical structures and get NMR chemical shifts in ChemDraw. Second, they learn how to perform literature searches including online databases to obtain pKa values and experimental 13C NMR data of the acids. Third, they use Microsoft Excel to perform data processing and analysis. Fourth, they interpret the results with concepts that they have learned in organic chemistry. At this step, a list of the above-mentioned concepts and group discussions would be helpful. The instructor may need to provide technical guidance throughout the project including introduction of the software, literature search, and chemical databases. It is also recommended that any necessary adaptation to this material be made to meet specific teaching needs. Finally the instructor to the students should emphasize that the last decades have seen a number of successful applications of computer-based tools in chemistry. However, at the same time, chemistry has been and will be based on experiment and maybe that is the reason why it is a fascinating science.
www.JCE.DivCHED.org
•
Acknowledgment The author would like to thank reviewers for constructive comments. Literature Cited 1. Cambridgesoft, ChemDraw Ultra 1985–2000, Appendix F: How ChemNMR Pro Works. http://www.cambridgesoft.com/ products (accessed Jun 2005). 2. (a) Hammett, L. P.; Pfluger, H. L. J. Am. Chem. Soc. 1933, 55, 4079. (b) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96. (c) Burkhardt, G. N.; Ford, W. G. K.; Singleton, E. J. Chem. Soc. 1936, 17. 3. Wang, H.; Dai, D.; Liu, Y.; Guo, Q. Tetrahedron Lett. 2002, 43, 7527 and references cited therein. 4. Brown, H. C.; McDaniel, D. H.; Hafliger, O. In Determination of Organic Structures by Physical Methods; Braude, E. A., Nachod F. C., Eds.; Academic Press: New York, 1955; p 588. 5. (a) Abraham, R. J.; Loftus, P. Proton and Carbon-13 NMR Spectroscopy, an Integrated Approach; John & Wiley Sons: Chichester, United Kingdom, 1983; p 24. (b) Barchiesi, E.; Bradamante, S.; Ferraccioli, R.; Pagani, G. A. J. Chem. Soc. Perkin Trans. 1990, 2, 375. 6. Kosugi, Y.; Furuya, Y. Tetrahedron 1980, 36, 2741. 7. Spectral Database for Organic Compounds, SDBS Home Page. http://www.aist.go.jp/RIODB/SDBS/menu-e.html (accessed Jun 2005).
Vol. 82 No. 9 September 2005
•
Journal of Chemical Education
1341
