Laboratory Experiment pubs.acs.org/jchemeduc
Computational Chemistry in the Undergraduate Laboratory: A Mechanistic Study of the Wittig Reaction Birgit Albrecht* Chemistry Department, Loyola University Maryland, Baltimore, Maryland 21210, United States S Supporting Information *
ABSTRACT: The Wittig reaction is one of the most useful reactions in organic chemistry. Despite its prominence early in the organic chemistry curriculum, the exact mechanism of this reaction is still under debate, and this controversy is often neglected in the classroom. Introducing a simple computational study of the Wittig reaction illustrates the mechanistic uncertainty in this reaction and also demonstrates the use of computational methods in chemistry. This exercise is designed to be used with the Hyperchem software package, but can easily be adapted to other applications, both commercial and freeware. Learning outcomes focus on specific details of the Wittig reaction, the uncertainty of reaction mechanisms in general, and thermodynamic aspects of reactions. KEYWORDS: Computational Chemistry, Organic Chemistry, Physical Chemistry, Upper-Division Undergraduate, Laboratory Instruction, Hands-On Learning/Manipulatives, Computer-Based Learning, Molecular Modeling, Molecular Properties/Structure
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INTRODUCTION The Wittig reaction1 is one of the most versatile and useful synthetic applications in organic chemistry, and plays a vital role in research, as well as in the chemistry classroom. The reaction forms a CC double bond from a CO bond using a phosphorus ylide reagent with high E/Z selectivity. Unlike many other organic reactions, it does not give product mixtures of substituted isomers. Despite its prominence in organic chemistry and a Nobel Prize for Georg Wittig in 1979,2 the exact mechanism is still under debate. Both experimental3−5 and computational6−10 methods have been used to address this question, but the exact mechanism has still not been settled. Almost all undergraduate organic chemistry courses teach the Wittig reaction early in the curriculum. However, the controversy of the proposed mechanism is rarely addressed and students often end up with a false confidence in mechanistic details of organic reactions. A computational study of the Wittig reaction as a lab exercise is described involving molecular modeling and computer simulations. Not only does this give students early exposure to computational research methods that are becoming increasingly popular and important, but it also illustrates that mechanisms are only theories that have to be examined carefully and critically, and confirmed with experimental data. Computational exercises encourage undergraduates to think about other reaction mechanisms in the same critical way. In recent years, computational exercises have become more common and have been added to almost all aspects of chemistry laboratories, ranging from physical chemistry calculations exploring kinetics of reactions11 to quantum © XXXX American Chemical Society and Division of Chemical Education, Inc.
based modeling exercises studying molecular geometries, calculating orbitals, and predicting spectra.12 Studies of organic reactions have so far been limited to the Diels−Alder13 and the Ritter14 reactions. The Diels−Alder exercise focuses on the endo versus exo products, and does very little to address the actual reaction. The Ritter reaction study has students calculate enthalpies of formation for reactants and products to predict a reaction profile, but does not address the mechanism of the reaction. This exercise adds substantively to the range of student-oriented exercises already published because it illustrates mechanistic uncertainties and, therefore, shows students the importance of critical evaluations and ongoing research of reaction mechanisms not acknowledged in previously published exercises. Furthermore, the exercise actually simulates a reaction and provides a visual for how bonds are formed and broken during a reaction.
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BACKGROUND The two potential mechanisms for the Wittig reaction can be summarized as a classical or an alternative mechanism. The classical mechanism (Figure 1), which is still taught in organic chemistry classes, is based on a charged ylide and a charged intermediate known as a zwitterion. The zwitterion is also often referred to as the betaine intermediate, which then rearranges to form an oxaphosphetane molecule. Experimental data and NMR studies of the reaction showed that the betaine intermediate may not occur and that this classical mechanism
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Laboratory Experiment
EXERCISE Students work in pairs. Models of both reactants, the carbonyl and the ylide, and the resulting products are built and optimized. Students use low level ab initio methods for optimizations, as this keeps calculation times within acceptable limits for a lab exercise. Energies (heats of formation) are calculated for the reactants and the products and the heat of the reaction is computed. Students then build models for the two proposed transition states for the different mechanisms. This encourages students to think through both mechanisms and their merits. They also had to appreciate that transition states are inherently high in energy, and traditional energy minimizations would not result in a valid transition state structure. Energies are calculated for transition states from both mechanisms, allowing for a thermodynamic comparison. Hyperchem allows for a basic simulation of a reaction mechanism by the collision of the reactants under the correct conditions. For the Wittig reaction both the carbonyl and ylide reactants are initially present as separate molecules. A simulation is started with the following parameters: velocity 90 A/ps, heat time 0 ps, run time 0.08 ps, cool time 0.1 ps, step size 0.001 ps, starting temperature 0 K, simulation temperature 1000 K, final temperature 500 K, and temperature step 100 K. The simulation is updated on the screen and viewed as it proceeds and is recorded into a movie file. The ‘re-bond system’ command in the script editor shows the newly formed bonds once the simulation is complete. With this, students visualize how molecules approach each other for a reaction, and how conditions, as well as the orientation of the molecules, are critical in this process. Initial simulations are carried out with in vacuo conditions. Students think about the effect this might have on the reaction mechanism through ongoing discussions and pre-lab questions. Once this solvent problem is identified, they repeat the calculation with continuum solvent parameters to model a solvent effect and compare the results. The typical solvent for this reaction, tetrahydrofuran (THF), can be modeled with a dielectric constant of 7.4 and a solvent probe radius of 2.52 Å. Finally, energy profiles for the two different reaction mechanisms are predicted. The reaction simulations are carried out as described above; however, the simulation times are gradually reduced. This meant that the reaction would not always go to completion. A reaction energy profile is plotted by stopping the reaction at several different points and calculating single point energies. A minimum of 15 data points is recommended to get a smooth line. Simulations are carried out with the actual reactants or with charged reactants to force a simulation of the two different mechanisms. Detailed instructions, as well as pre-lab questions and a lab report sheet, are available in the Supporting Information.
Figure 1. Classical Wittig reaction mechanism.
does not account for all possible observations of the Wittig reaction.3,15 The alternative mechanism (Figure 2) involves an uncharged reaction sequence in which the oxaphosphetane is formed
Figure 2. Alternative Wittig reaction mechanism.
directly through an asynchronous cyclo-addition.3 Experimental data found that a betaine intermediate has never been observed, the ratio of products from a betaine mechanism would be less than the ratio of a cyclo-addition mechanism, and there are significant differences in reaction rates. Recent high-level computational research studies16 also found no evidence for betaine intermediates, and only gauche intermediates for certain reactants in vacuo and tetrahydrofuran (THF) simulations. This suggested that the type of mechanism for the Wittig reaction may depend on steric effects of the reactants, as well as solvent effects. In general, there is still much interest in the actual mechanism of the Wittig reaction, though the focus has become increasingly narrow and specialized.
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EXERCISE OVERVIEW In this exercise, computational chemistry methods are used to predict structures and calculate molecular properties, such as bond lengths and energies of different reaction intermediates. While to some degree this exercise is a lower-level implementation of an earlier study,6 it also investigates a less specific system and offers a more general overview of the Wittig mechanism. The higher-level study focused on identifying and optimizing transition states for a specific ylide and aldehyde combination with bulky chiral substituents to compare the two potential reaction pathways and built a reaction profile based on only four data points (reactant, transition state 1, transition state 2, and product). This exercise, however, provides a much more visual and detailed illustration of the pathways and the ways bonds are formed that is more suitable for undergraduates. While the accuracy of the transition state and energies do not match the high-level studies, similar reaction profiles are obtained, clearly showing students the mechanistic uncertainties of reaction mechanisms.
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HAZARDS There are no hazards involved in this computational exercise. RESULTS AND ASSESSMENT Currently, this experiment is included in a series of exercises to introduce computational chemistry in a Physical Chemistry 2 laboratory. All students have completed a two-semester organic chemistry course, and performed a wet Wittig reaction in an organic lab. Calculations are carried out on University computers during a computational lab period. The lab period B
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Figure 3. Reaction profile for the two different Wittig mechanisms from student data.
• Literature searches for proposed mechanisms and transition states for a reaction. • Differences in energies when using different force fields. • Applications of computational chemistry techniques and their limitations. • The difference between heats of formations and the heat of a reaction. • Mechanisms are only theories, and not all memorized knowledge can be relied upon under all conditions. Critical thinking and experimental data are essential to chemistry. The overall student learning aims for this course included the ability to use computational methodologies in research with an appreciation of their advantages and limitations, and critical thinking and analysis of experimental data. Therefore, the emphasis of this exercise was focused on the last three concepts listed above, with evaluation questions in the pre-lab questions and the lab report, as well as the CHEMX23 perception of chemistry survey conducted at the end of every semester to assess whether these pedagogical goals had been met. The CHEMX survey evaluated student perception of seven different clusters (effort, concepts, math link, reality link, outcome, laboratory, and visualization). Introducing this exercise led to a 2% increase in the visualization and reality clusters, 4% in laboratory, and 6% in math link, with the remaining three clusters stable. Questions asked in lab report included information on the mechanism and solvents used, while contemplative questions asked students to define what a reaction mechanism is, how they are usually proposed, if they think one of the two Wittig mechanism is more likely and why, whether any mechanism can be ruled out as wrong or suggest another one, how this exercise has changed their perception on reaction mechanism and their validity, and how this exercise has changed their view on computational chemistry. Specific student feedback included a much greater appreciation for the use of modern computational tools, even in “oldfashioned” organic chemistry, and surprise at how very different results could be obtained with only slight differences in setup. Students repeatedly commented how before this exercise they did not appreciate the often speculative nature of some reaction mechanisms, though they realized now that some mechanisms
is 3 h and 50 min, and the exercise can easily be completed during this time, with spare time for pre- and post-lab discussions, and time to repeat calculations under different conditions. The exercise has been run for two years, with typical enrollments of 5−10 students. After the lab, students were required to complete a lab report asking them about data from their simulation, as well as their perception of computational chemistry and reaction mechanisms. In general, the exercise was run in a POGIL style.17 Students were given an initial set of instructions to run the calculations. During the lab they were encouraged to question their results through constant discussion with the instructor and each other to test the validity of their results. A quick review of the mechanism of the Wittig reaction at the beginning of the lab period was found to be greatly beneficial, and was assigned as part of the pre-lab questions. Allowing students to work in pairs also greatly stimulated the discussion in the lab. Student results showed no clear preference for a specific pathway. The difference between the two profiles was relatively minor, but showed saddle points for transitions states at different times during the reaction. An example of a reaction profile calculated by a student is shown in Figure 3. While student results usually differed slightly in magnitude, the overall trends were generally observed. This forced students to think critically about the probabilities of the two mechanisms and led them to conclude that no definite statement could be made about the pathway. They, therefore, gained a greater understanding and appreciation for the theoretical nature of some reaction mechanisms. The program used was the Hyperchem18 software package, but this exercise could easily be adapted for other software packages, including Spartan,19 Accelyrs Discovery Studio20 or even free-ware such as GAMES/WebMO,21 or Tinker.22 Transition states could be identified either via a transition state search or obtained by students through literature searches from sources such as Robiette et al.,9 depending on the available software. The addition of computational techniques to traditional wet chemistry experiments provided a much better insight and understanding into the mechanics of chemistry. More specifically, depending on the desired learning aims, a wide variety of different concepts could be emphasized with this exercise: C
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(12) Johnson, L. E.; Engel, T. Integrating computational chemistry into the physical chemistry curriculum. J. Chem. Educ. 2011, 88, 569− 573. (13) Rowley, C. N.; Woo, T. K.; Mosey, N. J. A computational experiment of the endo versus exo preference in a Diels−Alder reaction. J. Chem. Educ. 2009, 86, 199. (14) Hessley, R. K. Computational investigations for undergraduate organic chemistry: Predicting the mechanism of the ritter reaction. J. Chem. Educ. 2000, 77, 202. (15) Vedejs, E.; Marth, C. F. Mechanism of Wittig reaction: Evidence against betaine intermediates. J. Am. Chem. Soc. 1990, 112, 3905− 3909. (16) Alagona, G.; Ghio, C. Dependence of the wittig reaction mechanism on the environment and on the substituents at the aldehyde group and at the phosphonium ylide. Int. J. Quantum Chem. 2010, 110, 765−776. (17) Spencer, J. N.; Moog, R. S. The Process Oriented Guided Inquiry Learning Approach to Teaching Physical Chemistry. In Advances in Teaching Physical Chemistry; American Chemical Society: Washington, DC, 2007; Vol. 973, pp 268−279. (18) HyperChem, 8.0; Hypercube: Gainesville, FL. (19) Spartan; Wavefunction, Inc.: Irvine, CA. (20) Discovery Studio: Accelrys: San Diego, CA. (21) Schmidt, M. W.; Baldridge, K. K.; Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen, J. H.; Koseki, S.; Matsunaga, N.; Nguyen, K. A. General atomic and molecular electronic structure system. J. Comput. Chem. 1993, 14, 1347−1363. (22) Ren, P.; Wu, C.; Ponder, J. W. Polarizable atomic multipolebased molecular mechanics for organic molecules. J. Chem. Theory Comput. 2011, 7 (10), 3143−3161. (23) Grove, N.; Bretz, S. L. CHEMX: An instrument to assess students’ cognitive expectations for learning chemistry. J. Chem. Educ. 2007, 84, 1524.
may be more speculative than others, indicating a successful accomplishment of the pedagogical aims of this exercise. Other potential uses of this exercise include the organic chemistry lecture class, upper-level synthesis classes, theoretical chemistry classes, or an addition to the traditional Wittig lab. It has proven highly beneficial to allow for a class discussion on the assignment, its relevance and objectives and to provide some initial guidance. Depending on the availability of hardware and software, it could even be assigned as an outof-class homework as long as enough guidance in the critical evaluation of the observation is given.
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ASSOCIATED CONTENT
S Supporting Information *
Detailed student instructions, pre-lab questions and lab report questions. 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 Special thanks to Dr. Jesse More and Dr. Kate Bowdy for their helpful comments and suggestions in the development of this exercise and preparation of this article.
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REFERENCES
(1) Wittig, G.; Schollkopf, U. Triphenylphosphinemethylene as an olefin-forming reagent. I. Chem. Ber. 1954, 97, 1318−1330. (2) Wittig, G. From diyls via ylides to my idyll (Nobel lecture). Angew. Chem. 1980, 92, 671−675. (3) Maryanoff, B. E.; Reitz, A. B.; Mutter, M. S.; Whittle, R. R.; Olofson, R. A. Stereochemistry and mechanism of the Wittig reaction. Diasteromeric reaction intermediates and analysis of the reaction course. J. Am. Chem. Soc. 1986, 108, 7664−7678. (4) McEwen, W. E.; Ward, W. J. A general hypothesis for the mechanism of the Wittig reaction. Phosphorus, Sulfur Silicon Relat. Elem. 1989, 41, 393−398. (5) Vedejs, E.; Marth, C. F. Mechanism of the Wittig reaction: the role of substituents at phosphorus. J. Am. Chem. Soc. 1988, 110, 3948− 3958. (6) Alagona, G.; Ghio, C. Stepwise versus concerted mechanisms in the Wittig reaction in vacuo and in THF: The case of 2,4-dimethyl-3pyrrol-1-yl-pentanal and triphenylphosphonium ylide. Theor. Chem. Acc. 2009, 123, 337−346. (7) Mari, F.; Lahti, P. M.; McEwen, W. E. Molecular modeling of the Wittig reaction. 3. A theoretical study of the Wittig olefination reaction: MNDO-PM3 treatment of the Wittig half-reaction of unstabilized ylides with aldehydes. J. Am. Chem. Soc. 1992, 114, 813−821. (8) McEwen, W. E.; Mari, F.; Lahti, P. M.; Baughman, L. L.; Ward, W. J., Jr. Mechanisms of the Wittig reaction. ACS Symp. Ser. 1992, 486, 149−161. (9) Robiette, R.; Richardson, J.; Aggarwal, V. K.; Harvey, J. N. Reactivity and selectivity in the Wittig reaction: A computational study. J. Am. Chem. Soc. 2006, 128, 2394−2409. (10) Yamataka, H.; Nagase, S. Theoretical calculations on the Wittig reaction revisited. J. Am. Chem. Soc. 1998, 120, 7530−7536. (11) Marzzacco, C. J.; Baum, J. C. Computational chemistry studies on the carbene hydroxymethylene. J. Chem. Educ. 2011, 88, 1667− 1671. D
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