Modeling SN2 and E2 Reaction Pathways and Other Computational

Aug 15, 2013 - To prepare students for future application of these methods, ... isomers,(9, 10) and (4) generating transition states and hypothetical ...
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Laboratory Experiment pubs.acs.org/jchemeduc

Modeling SN2 and E2 Reaction Pathways and Other Computational Exercises in the Undergraduate Organic Chemistry Laboratory Clifford M. Csizmar, Jeremy P. Daniels, Lauren E. Davis, Tyler P. Hoovis, Karen A. Hammond, Owen M. McDougal, and Don L. Warner* Department of Chemistry and Biochemistry, Boise State University, Boise, Idaho 83725-1520, United States S Supporting Information *

ABSTRACT: Computational chemistry techniques have become increasingly important tools for chemists seeking to address scientific questions. As such, it is important that undergraduate chemistry students develop competence in this emerging field of chemistry. One strategy to gain proficiency involves exposing students to computational methods of increasing depth and complexity during each year of their laboratory curriculum, rather than solely at late stages of their education. The computational chemistry exercises described herein are designed to be completed in one introductory-level organic chemistry laboratory period, and they build upon concepts covered in traditional organic lecture and lab curricula. Students generate electrostatic potential maps for substituted acetic acids to analyze bond polarity and pKa, model acetate to explore resonance, and conduct conformation searches for monosubstituted cyclohexanes to examine the influence of sterics on conformational preference. They also generate reaction coordinate diagrams for substitution and elimination reactions between 2-bromobutane and various alkoxide bases. Students are asked to examine the energetics of starting materials, possible products, and theoretical transition states. All aspects of the exercises align with traditional topics, and thus reinforce their significance. KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Computer-Based Learning, Computational Chemistry, Conformational Analysis, Elimination Reactions, Molecular Modeling, Resonance Theory all four “mini experiments” are described in significant detail in the Supporting Information, the first three are adaptations of published procedures.7−10 Thus, this publication places more emphasis on the fourth, namely, the examination of the processes occurring during substitution and elimination reactions of (R)-2-bromobutane and alkoxide nucleophiles and bases. In the organic chemistry laboratory schedule, these exercises work well in a single, stand-alone lab session. However, they have added value when conducted during the final week of a three-week sequence that focuses on substitution and elimination reactions. In the first week, students conduct substitution reactions on a variety of alkyl halides with the intent to determine which structural features and reaction conditions favor an SN1 or SN2 pathway.11 During the second week, students use gas chromatography to determine the ratio of products formed in reactions between 2-bromoheptane and several alkoxides (methoxide, ethoxide, isopropoxide, secbutoxide, or tert-butoxide).11 Using these ratios, students are able to examine the influence of the nucleophile or base steric hindrance on the reaction pathway (SN2 or E2), as well as elimination product distribution (i.e., 1-heptene, cis-2-heptene, or trans-2-heptene). In the third and final week of the sequence, students computationally repeat the second week’s experiment

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omputational chemistry techniques are of increasing prevalence and importance in modern organic chemistry. To prepare students for future application of these methods, opportunities to integrate computational techniques throughout the undergraduate chemistry curriculum were sought; the introductory-level organic chemistry lab is the focus of this work and the corresponding Supporting Information. Computational chemistry has been used as an instructional aid for a multitude of essential organic chemistry concepts, as demonstrated by several excellent workbooks and numerous literature reports. A relevant subset of these experiments uses modeling to amalgamate classroom instruction and laboratory experiments. Examination of reaction intermediates, transition states, and conformational preferences has been used to determine reaction pathways and to correlate theoretical data with physical and spectroscopic observations.1−6 The projects described herein (and in the Supporting Information) give students a thorough introduction to a variety of computational and modeling techniques that are applicable to several scientific problems. Designed to be completed in one lab period, students are exposed to four different modeling practices: (1) generating electrostatic potential maps,7−9 (2) evaluating bond distances and atomic charges,9 (3) evaluating energy differences of conformational isomers,9,10 and (4) generating transition states and hypothetical reaction coordinate diagrams for several related chemical reactions. Although © XXXX American Chemical Society and Division of Chemical Education, Inc.

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capabilities, and facilitate a deeper understanding of the associated chemical topics. Please see the Supporting Information for a detailed description of the adaptation of these previously published exercises. In section four, students are assigned a particular alkoxide base or nucleophile of increasing steric bulk (methoxide, ethoxide, isopropoxide, or tert-butoxide) and asked to investigate the reaction between this reagent and (R)-2bromobutane. They begin by building models and optimizing the geometries of the starting materials and SN2 and E2 reaction products. Students calculate and combine semiempirical AM1 heats of formation with SM5.4 solvation energies12 to estimate the reaction energies in water for the two reaction pathways (aqueous solvation energies are used to simulate the effect of a polar medium on the reaction energies). Students record their data on electronic answer sheets (see the Supporting Information). Next, students are provided with SN2 and E2 transition-state models of hydroxide reacting with (R)-2-bromobutane. They modify these models by changing the hydroxide into the assigned alkoxide and then search for the corresponding AM1 transition state (Figure 1A). Aqueous solvation energies are

using (R)-2-bromobutane in place of the 2-bromoheptane. Students are assigned a specific alkoxide base and then perform various calculations on the starting materials, transition states, and products of possible SN2 and E2 reactions. The energy calculations aim to help students conceptualize the various factors that determine whether a reaction will proceed through a substitution or elimination mechanism. Additionally, students conduct frequency calculations to allow visualization, through animation, of the bond making and breaking as the reaction progresses (and to verify that their structures are valid transition states with a single imaginary frequency). Thus, students are provided with additional insight into these important organic reactions. These projects also serve a curriculum-wide effort to present computational chemistry to students annually. Table 1 Table 1. Summary of Computational Chemistry Exposure Across the Curriculum Curriculum Year

Laboratory Course

First-year

General Chemistry

Second-year

Organic Chemistry Physical Chemistry Biochemistry

Advanced Advanced

Topics Covered Introduction to computational software, building molecules, viewing molecular vibrations Electrostatic potential maps, natural charges, resonance, transition states, conformations Molecular orbitals, vibrational and rotational spectra, basis sets Enzyme−ligand binding, docking studies, enzyme and active site conformations

highlights the concepts and techniques presented at each stage of the curriculum. As expected, the exposure increases in depth and complexity as a student progresses. It is anticipated that such an approach will provide students with the familiarity necessary to be proficient in this expanding area of chemistry, and the projects described here fit perfectly into this pedagogy.

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Figure 1. Two views of the theoretical transition state of the SN2 reaction between methoxide and (R)-2-bromobutane leading to (S)-2methoxybutane: (A) ball-and-stick model of the transition state; (B) space-filling model of the transition state. Both views are shown in the same orientation, and identical atoms are labeled as such.

EXPERIMENTAL PROCEDURE

Organization of Laboratory Sections

The time allotted for each experiment in organic chemistry laboratory sections is 3 h and 40 min. Students are each provided access to a computer with the program Spartan ’04 Essential installed. All students work individually for some portions of the experiment and as part of a group for others, with the instructor providing help and answering questions as needed. It is important to note that (1) a tutorial for manipulating the computational software was integrated into the experiment procedure and (2) the experiment was tested on a newer version of Spartan (Spartan ’10) and only one minor modification to the procedure was required (see the Supporting Information).

obtained as before. AM1 frequency calculations are performed to verify that each model was a true transition state and to provide students with an animation of the reaction, clearly showing deprotonation of the starting material leading to elimination or the characteristic “backside attack” of the substitution pathway. Students are asked to view the animations using ball-and-stick models (Figure 1A) and space-filling models (Figure 1B). The latter clearly shows the steric interactions that arise during the elimination and substitution processes and helps students understand these interactions. At this point in the procedure, students obtain all the numerical data necessary to generate a theoretical reaction coordinate diagram, which is the next focus of this section. Students are given a template spreadsheet to fill in using their calculated data. The spreadsheet used the students’ values to generate graphs resembling reaction coordinate diagrams (Figure 2). The reactants are set to a relative energy of 0 kcal/mol, placing them on the horizontal axis, whereas the energies of the transition states and products are scaled according to their calculated energy. Thus, students gained additional exposure, beyond the lecture, to topics such as reaction thermodynamics, reaction kinetics, and alkene stability. The results are pooled and a comprehensive copy is redistributed back to all students (Table 2). This allows each

Overview of Laboratory Experiment

The computational exercises are divided into four distinct, yet pedagogically related, sections, each directed toward answering a specific question using computational techniques. The first three sections, which are based on published procedures, involve (1) calculating the theoretical pKa of acetic acid and viewing its electrostatic potential map,7,8 (2) examining the resonance of the acetate anion through measurement of the C− O bond lengths and formal charges on the oxygen atoms,9 and (3) exploring the preference for an equatorial conformation in monosubstituted cyclohexanes.9,10 Each of these exercises serves to introduce students to Spartan, explore some of its B

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consistent with expectations or observations from the previous week’s “wet lab” experiment with 2-bromoheptane. Students were made aware of the fact that the calculations they performed were brief and greatly simplified when compared to those used in a typical research setting, and that more rigorous calculations were not only beyond the scope of the organic lab, but were also not feasible due to time constraints. When possible, an attempt was made to offer explanations for the lack of agreement (or to point interested students to references that provided more detailed explanations of basis sets and calculation methods). Thus, students understood that discrepancies may arise, but the point of the exercise was to introduce them to the computational methods available to chemists. Sampling of Student Results

Figure 2. Example of the reaction coordinate diagram generated by students with (R)-2-bromobutane and methoxide as the base: SM is starting material, TS is transition state, and Prod is products.

Figures 1 and 2 show student results from the SN2 and E2 calculations involving 2-bromobutane and methoxide. Table 2 includes typical pooled data from the groups.13 Students were able to observe the animated transition state for each substitution and elimination scenario, as well as view the steric interactions involved (via a space-filling model). The reaction coordinate diagram clearly showed the reaction expected to have the most stable transition state, as well as the products predicted to be the most stable overall. In general, the pooled data correlated nicely with several concepts learned within both the organic chemistry lecture and lab courses. For example, the calculations were in agreement with expectations for the following: (1) the substitution products are thermodynamically more favored than the elimination products, (2) alkene stability follows what is expected (trans-2-butene is more stable than cis, which is more stable than 1-butene), (3) the SN2 transitionstate energy is greater for all alkoxide bases, indicating that formation of the elimination products is kinetically preferred, (4) for a given base, the difference in energy between the SN2 and E2 transition states increases as the steric bulk of the alkoxide increases, indicating that elimination is preferred with more hindered alkoxides. There was some disagreement between calculations and expected results. Students should expect, for example, the formation of 1-butene to become increasingly favorable as the alkoxide bases become stronger, and that 1-butene should be the major product in the reaction with tert-butoxide.14 The calculations did not yield transition-state energies that were consistent with these expectations. The transition state that led to the formation of 1-butene was higher in energy than the one leading to trans-2-butene. The discrepancies provided opportunities to inform students of some benefits and drawbacks of computational chemistry, as well the factors that were involved in choosing a proper calculation method and basis set. In the present calculations, for example, a basis set that was more properly suited for atoms with nonbonding electrons might be more appropriate (e.g., those that incorporate diffuse functions), as would choosing a method that allows for proper correction of solvent polarity. In considering calculation methods, however, students were cautioned that the accompanying increase in calculation time might render the alternative method impractical.

Table 2. Relative Energies of Transition States and Products for SN2 and E2 Reactions between (R)-2-Bromobutane and Alkoxide Bases

a

Computational chemistry calculations were conducted using Spartan ’04 Essential. Semiempirical AM1 heats of formation were combined with SM5.4 solvation energies to estimate the reaction energies in a polar environment. These values, which were referred to as “Eaq” in the Spartan program, were used in all calculations. bActivation energies (ΔE⧧) were calculated as follows: ΔE⧧= E(transition state) − E(starting materials), where E(starting materials) is the sum of the individual energies for (R)-2-bromobutane and the alkoxide. cChange in reaction energies (ΔE°) were calculated as follows: ΔE° = E(products) − E(starting materials), where E(products) includes the individual energies for bromide, the alkene, and the alcohol. For the SN2 reactions, the energies for (S)-2-alkoxybutane and bromide were used for E(products). E(starting materials) was calculated as before.

student to view the results of the other compounds and to see the broader trends revealed by the experiment, specifically the effect that increasing the steric hindrance of the base has on the expected reaction product.

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HAZARDS There are no hazards associated with this lab.

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CONCLUSIONS This laboratory experiment introduced students to computational and modeling techniques while simultaneously reinforcing the following lecture topics: (1) the basis of pKa, (2)

RESULTS AND CONCLUSIONS When following the directions set forth in the experimental procedure, students obtained results that were reasonably C

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(10) Hehre, W. J.; Shusterman, A. J.; Nelson, J. E. The Molecular Modeling Workbook for Organic Chemistry; Wavefunction, Inc.: Irvine, CA, 1998; pp 78−79. (11) Mohrig, J. R.; Hammond, C. N.; Schatz, P. F.; Morrill, T. C. Modern Projects and Experiments in Organic Chemistry: Miniscale and Standard Taper Microscale, 2nd ed.; W. H. Freeman and Company: New York, NY, 2003; pp 47−55, 67−71, 77−81. (12) Spartan ’04 Essential uses the SM5.4 aqueous solvent correction. (13) In the first three exercises, which are described in detail in the Supporting Information, student results matched reasonably well with expectations based on previously published procedures and literature data. (14) Bartsch, R. A.; Závada, J. Stereochemical and Base Species Dichotomies in Olefin-Forming E2 Eliminations. Chem. Rev. 1980, 80, 453−494.

resonance, (3) the differences between equatorial and axial substituents in chair-conformation cyclohexanes, and (4) the reaction coordinate diagrams of substitution and elimination reactions. The justification for this lab is twofold: (1) there is a rapidly growing presence of computational chemistry in modern chemistry and (2) based on our experience, students typically exhibit difficulty in understanding the topics examined in this lab. A formal assessment of the experiment’s impact on student learning was not undertaken, but questions on end-ofsemester student evaluations demonstrated that students perceived the computational exercises as beneficial to their learning. Additionally, the same evaluations demonstrated that students had a favorable opinion of the software and calculations. As a result, these exercises have been conducted by over 750 first-semester organic chemistry laboratory students since 2008, where it serves a larger computational chemistry pedagogy.

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ASSOCIATED CONTENT

S Supporting Information *

Experimental procedures, instructor notes, Spartan files, and answer keys. This material is available via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge the financial support of the Boise State Department of Chemistry and Biochemistry for the computational resources necessary for completion of this laboratory experiment.

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REFERENCES

(1) Hessley, R. K. Computational Investigations for Undergraduate Organic Chemistry: Predicting the Mechanism of the Ritter Reaction. J. Chem. Educ. 2000, 77, 202−203. (2) Clauss, A. D.; Nelsen, S. F. Integrating Computational Molecular Modeling into the Undergraduate Organic Chemistry Curriculum. J. Chem. Educ. 2009, 86, 955−958. (3) Cook, A. G.; Kreeger, P. K. Reaction of Morpholine with t-Butyl Acetoacetate: A Study in Kinetic vs Thermodynamic Control, Product Identification, and Molecular Modeling. J. Chem. Educ. 2000, 77, 90− 92. (4) Jones, M. B. Molecular Modeling in the Undergraduate Chemistry Curriculum. J. Chem. Educ. 2001, 78, 867−868. (5) Martin, N. H. Integration of Computational Chemistry into the Chemistry Curriculum. J. Chem. Educ. 1998, 75, 241−243. (6) Stokes-Huby, H.; Vitale, D. E. Coupling Molecular Modeling to the Traditional “IR-ID” Exercise in the Introductory Organic Chemistry Laboratory. J. Chem. Educ. 2007, 84, 1486−1487. (7) Shusterman, G. P.; Shusterman, A. J. Teaching Chemistry with Electron Density Models. J. Chem. Educ. 1997, 74, 771−776. (8) Hehre, W. J. A Guide to Molecular Mechanics and Quantum Chemical Calculations; Wavefunction, Inc.: Irvine, CA, 2003; pp 478− 480. (9) Hehre, W. J.; Shusterman, A. J.; Huang, W. W. A Laboratory Book of Computational Organic Chemistry; Wavefunction, Inc.: Irvine, CA, 1998; pp 45−50, 63−64, 129−130. D

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