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1340 Journal of Chemical Education Vol. 82 No. 9 September 2005 www.JCE.DivCHED.org

Nuclear magnetic resonance spectroscopy (NMR) is apowerful tool to solve the structures of organic compounds.ChemDraw by Cambridgesoft offers a new feature to pre-dict 13C and 1H NMR chemical shifts of organic compounds(1) that has been welcomed by the chemistry community.ChemDraw identifies a molecules key substructure that pro-vides the base value for the estimated shift. The software viewsthe remaining parts of the molecule as substituents of thesubstructure. Each substituent adds to or subtracts from thebase shift of the substructure to which it is attached. Addi-

tivity rules determine the increment of each contribution. Thedata set for 1H NMR shift tool currently contains 700 basevalues and about 2000 increments. The 13C NMR tool isbased on 4000 parameters.

Linear correlation between the logarithms of rate con-stants and pK a values of substituted benzoic acids was inde-pendently discovered by Hammett and Burhardt in the 1930sand has been used extensively as a means of estimating therelative polarity of substituents(2). The Hammett valuefor the substituent is a reflection of the electronic effect of that substituent on the dissociation constant of the substi-tuted benzoic acid. Similar correlation research has been per-formed among physical properties (NMR, UV, IR, electronic

potentials, etc.) and chemical reactivity of organic compoundsto gain a better understanding and prediction of the reactiv-ity (3). Today an appreciation of the relationship betweenstructure and reactivity is central to modern organic chemis-try. Consequently, organic chemists can usually predict

whether replacement of hydrogen by another group in a com-pound will be rate-increasing or rate-decreasing in a particu-lar reaction or will be in favor or disfavor of certain equilibriaprocesses.

The author was inspired to combine the two aspects to-gether to generate teaching materials for first-year organicchemistry students. Fifteen para-substituted benzoic acids(Scheme I) were chosen for several reasons: first, this systemhas historic importance as mentioned above; second, the sub-stituents represent a wide range of organic functional groups

with electron-withdrawing or electron-donating properties;third, only para-substitution was treated for simplicity. Thesecompounds were processed with the ChemDraw NMR toolto generate 13C NMR chemical shifts of C1 through C5(Scheme I). The data were then plotted against their pK a val-ues (4) in Microsoft Excel and a fairly good linear fit wasfound for pK a versus C1 with R 2 = 0.9412 (Table 1 and Fig-ure 1). Correlations with chemical shifts of other carbons didnot give useful results.

As seen above, in a series of structurally related com-

pounds13

C NMR chemical shift values could represent theelectronic nature of a certain carbon, further, representingthe polarity of substituents(5). It can be seen that C1 in thiscase is most sensitive to substituent effect.

Analysis of experimental13C NMR chemical shifts inthe same manner as above would provide a good evaluationof the ChemDraw NMR tool as well as validation of thisapplication. A literature search(6) gave a set of 13C NMR data of six para-substituted benzoic acids determined inDMSO-d 6 H2O (4 1, pH < 1) as listed in Table 1. SDBSdatabase(7) search gave another set of 13C NMR data of eightpara-substituted benzoic acids determined in DMSO-d6 aslisted in Table 1 (Several others were determined in CDCl3

and were not used here since NMR chemical shifts may beaffected by solvents). These two sets of data were plotted thesame way as above (Figure 1), givingR 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 bedue to the fact that ChemDraw NMR tool is mostly basedon organic solvents. Although the pK a values were obtainedin aqueous solution, these two sets gave good linear fits. It isinteresting to note that NMR data from DMSO H 2O andaqueous-based pK a values gave a relatively poor linear fit, which reflects the complexity of the molecular basis for theobserved substitution effects in the aqueous acidities of ben-zoic acids.

The chemical basis behind this correlation is at the very heart of organic chemistry: structurereactivity relationship.Deprotonation of benzoic acid gives the conjugate base, ben-zoate anion, which carries a negative charge (Scheme I). Inthis equilibrium the para-substituents on the phenyl ring play an important role by stabilizing or destabilizing the benzoateanions regarding the developed negative charge. An electron- withdrawing group stabilizes the anion by sharing partialnegative charge, thus giving a lower pK a value for a stron-ger acid. An electron-donating group, on the other hand,destabilizes the anion by further enriching electron density,thus giving a higher pK a value for a weaker acid. Transmit-ting a polar effect through the aromatic nucleus can involveboth inductive and resonance paths.

Application of ChemDraw NMR Tool: Correlationof Program-Generated 13 C Chemical Shifts and p K a Valuesof para-Substituted Benzoic AcidsHongyi Wang

Department of Chemistry, University of Florida, Gainesville, FL 32611VisiGen Biotechnologies, Inc., 2575 West Bellfort, Suite 250, Houston TX 77054;hwang@visigen1.com

Scheme I. Substituted benzoic acids.

CO 2H

X2

3

1

4

5CO 2

X

H

X NHMe, NMe 2 , NH 2 , OMe, OH, F, Me, Et, i -Pr,Cl, Br, H, CN, CO 2H, NO 2

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In this project the author has tried to bring together or-ganic chemistry concepts and techniques. It covers the fol-lowing important concepts: Hammett equation, acidbaseequilibrium theory, electronic nature of functional groups,inductive and resonance effects, structurereactivity relation-

ship, and NMR spectroscopy. It may also be used to intro-duce some basic research techniques: literature searches,database searches, and ChemDraw software usage. Theproject can be used as an assignment at the end of first-yearorganic chemistry class to review topics and explore new tech-niques. First, students learn how to draw chemical structuresand get NMR chemical shifts in ChemDraw. Second, they learn how to perform literature searches including online da-tabases to obtain pK a values and experimental13C NMR dataof the acids. Third, they use Microsoft Excel to perform dataprocessing and analysis. Fourth, they interpret the results withconcepts that they have learned in organic chemistry. At thisstep, a list of the above-mentioned concepts and group dis-cussions would be helpful. The instructor may need to pro-vide technical guidance throughout the project includingintroduction of the software, literature search, and chemicaldatabases. It is also recommended that any necessary adapta-tion to this material be made to meet specific teaching needs.

Finally the instructor to the students should emphasizethat the last decades have seen a number of successful appli-cations of computer-based tools in chemistry. However, atthe same time, chemistry has been and will be based on ex-periment and maybe that is the reason why it is a fascinatingscience.

Figure 1. Correlation of pK a values and C1 of para-substituted ben-zoic acids: (x, .... ) experimental DMSO-d6/H 20, ( , ) experi-mental DMSO-d6, ( , ) ChemDraw NMR tool.

3.3

3.5

3.7

3.9

4.1

4.3

4.5

4.7

4.9

5.1

116 118 120 122 124 126 128 130 132 134 136 138

p K

a

C1 (ppm )

pK a 0.0729 C1 13.48R 2 0.8455

pK a 0.0771 C1 14.007R 2 0.9657

pK a 0.0891 C1 15.61R 2 0.9412

Acknowledgment

The author would like to thank reviewers for construc-tive comments.

Literature Cited1. Cambridgesoft, ChemDraw Ultra 19852000, 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 Determi-nation 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 Spec-troscopy, 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).

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sdic AciozneBdetutitsbuS-arapnistfihSlacimehC)mpp(tfihSlacimehC

tneutitsbuS pK awarDmehClootRMN

latnemirepxE ad-OSMD 6

latnemirepxE bd-OSMD 6/

H2OeMHN 40.5 911 0. 7.611

eMN 2 30.5 1.021HN 2 29.4 6.021

eMO 74.4 9.221 2.321 4.221

HO 85.4 2.321 4.121

F 41.4 2.621 4.721 8.621

eM 43.4 6.721 1.821 6.721

tE 53.4 8.721i rP- 53.4 8.721

lC 99.3 7.821 7.921 2.921

rB 4 00. 6.921 031 0.

H 71.4 6.031 5.031NC 55.3 9.431

OC 2H 15.3 8.531

ON 2 44.3 7.631 5.631 1.631a fermorfataD 7 . b fermorfataD 6 .

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