Molecular Modeling of an Electrophilic Addition Reaction with

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Laboratory Experiment pubs.acs.org/jchemeduc

Molecular Modeling of an Electrophilic Addition Reaction with “Unexpected” Regiochemistry Katherine T. Best, Diana Li, and Eric D. Helms* Department of Chemistry, SUNY Geneseo, Geneseo, New York 14454, United States S Supporting Information *

ABSTRACT: The electrophilic addition of a hydrohalic acid (HX) to an alkene is often one of the first reactions learned in second-year undergraduate organic chemistry classes. During the ensuing discussion of the mechanism, it is shown that this reaction follows Markovnikov’s rule, which states that the hydrogen atom will attach to the carbon with fewer substituents while the halogen atom will attach to the carbon with more substituents. However, in the preparation of tropic acid, the reaction of HCl with atropic acid (2phenylpropenoic acid) does not follow this rule because it is a conjugated system. Molecular modeling of the possible carbocation intermediates suggests that the reaction follows a conjugate addition mechanism involving a 1,4-addition of HCl across the conjugated alkene and carboxyl group rather than addition across the alkene as students often first propose. PM3 semiempirical calculations are used to determine the energies of three possible carbocation intermediates. The energies obtained from the modeling suggest that the carbocation intermediate produced by the 1,4-addition is the most stable. KEYWORDS: Second-Year Undergraduate, Upper-Division Undergraduate, Organic Chemistry, Computer-Based Learning, Misconceptions/Discrepant Events, Addition Reactions, Alkenes, Mechanisms of Reactions, Molecular Modeling, Resonance Theory

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α,β-unsaturated aldehydes, ketones, and esters. It should not come as a surprise that students do not immediately make the connection to this reaction. The electrophilic addition of a hydrohalic acid (HX) to an alkene is often one of the first reactions of alkenes learned in second-year undergraduate organic chemistry classes. During classroom discussion of the mechanism, an explanation of why this reaction follows Markovnikov’s rule is described in terms of carbocation stability. A typical statement of Markovnikov’s rule is “...in the addition of HX to an alkene, the hydrogen atom adds to the carbon atom of the double bond that already has the greater number of hydrogen atoms.”2 If the reaction mechanism were a simple electrophilic addition reaction across the alkene as many students think, close examination of the reaction shown in Scheme 1 would reveal that this reaction as reported proceeds with the opposite regiochemistry than would be expected on the basis of Markovnikov’s rule; that is, the product of this reaction shows non-Markovnikov regiochemistry. A typical explanation of the observed regiochemistry is that the electron-withdrawing effects of the carboxyl moiety destabilize the “expected” tertiary benzylic carbocation intermediate relative to the homobenzylic primary carbocation. Molecular modeling of three of the possible carbocation intermediates (semiempirical or density functional theory (DFT)) suggests that the reaction follows a mechanism

INTRODUCTION The synthesis of tropic acid from acetophenone was reported by McKenzie and Wood1 in 1920. In a key step of the synthesis, atropic acid (2-phenylpropenoic acid) is reacted with hydrochloric acid in diethyl ether with heating for 24 h to produce βchlorohydratropic acid (3-chloro-2-phenylpropanoic acid), as shown in Scheme 1. Scheme 1. Reaction of Atropic Acid with Hydrochloric Acid Produces β-Chlorohydratropic Acid (3-Chloro-2phenylpropanoic Acid); Students Usually Expect αChlorohydratropic Acid (2-Chloro-2-phenylpropanoic Acid) To Be the Product

While instructors may recognize that conjugate addition is a likely mechanism that explains the regiochemical outcome of this reaction, students gravitate toward the more familiar addition to the carbon−carbon double bond, thinking of atropic acid as a styrene derivative rather than as an acrylic acid (propenoic acid) derivative. This is not unexpected since conjugate addition to α,β-unsaturated carbonyl compounds often focuses on reactions under alkaline conditions utilizing © XXXX American Chemical Society and Division of Chemical Education, Inc.

Received: July 1, 2016 Revised: April 4, 2017

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and Ogilvie13 in which the organic chemistry curriculum has been redesigned to present mechanistic tools before any reactions. The modeling of the addition of HCl to atropic acid in the current experiment supports this kind of thinking in that the answers students obtain via the modeling are used to explain the regiochemistry of a reaction using mechanistic thinking and skills rather than focusing on the reaction conditions. In relation to conjugate addition to α,β-unsaturated carboxylic acids under acidic conditions, Meek provided an experimentally based mechanistic exploration of the isomerization of maleic acid to fumaric acid with HCl.6 Other conjugate additions presented in this Journal are done under alkaline conditions,14−27 with the exception of that described by Markgraph et al.,28 who used acetic acid to catalyze a Michael addition, and none of these other conjugate additions are done on α,β-unsaturated carboxylic acids. The reaction under investigation in the experiment is reported to have taken 24 h using gaseous HCl,1 firmly placing this experiment in the category of a stand-alone exercise given the limitations of undergraduate laboratory courses. The molecular modeling experiment described here sets itself apart from the others that involve modeling of electrophilic additions to alkenes in that it models a reaction that, from a student standpoint, unexpectedly shows non-Markovnikov regiochemistry, making it a valuable addition to the other activities available in this Journal, as it uses molecular modeling to explore an “unexpected” experimental result. The experiment also helps to continue the development of student skills in drawing mechanisms using curved arrows to show bond formation and cleavage, drawing resonance structures including curved arrows, and using the results of molecular modeling to construct a hypothesis about the mechanistic course of a given reaction. Semiempirical computational methods are useful in many applications where qualitative insight about electronic structure and properties is sufficient. It is well-known that PM3 calculations inadequately describe carbocation geometry, particularly when it comes to formal primary carbocations, which are known to be better described as nonclassical, bridged cations.29,30 The qualitative ordering of the energies of the cations modeled at the PM3 level of theory is in agreement with higher-level ωB97X-D/6-31G* DFT calculations, even if the energy differences between the cations are overestimated by the PM3 calculation.

involving a 1,4-addition of HCl across the conjugated alkene and the carbonyl group rather than a simple addition across the alkene (in either the Markovnikov or non-Markovnikov sense). PM3 semiempirical calculations using Spartan Student3 are used to determine the energies of the carbocation intermediates. The data obtained from the modeling suggest that the O-protonated carbocation intermediate produced by the 1,4-addition is the most stable, leading to the observed product with the halogen attached to C3. Acrylic acid is known to undergo addition of HCl at the β-position as well to give 3chloropropanoic acid,4,5 suggesting that atropic acid should be considered an acrylic acid derivative rather than a styrene derivative. Further support for conjugate addition of HCl to unsaturated carboxylic acids can be found in this Journal.6 Previous molecular modeling exercises in this Journal span all areas of chemistry. Focusing on organic chemistry, Horowitz7 wrote that molecular modeling exercises could be divided into two broad categories: exercises tied to wet-chemistry experiments and stand-alone exercises. As an example of the former that involves modeling of electrophilic addition reaction mechanisms involving alkenes, Graham et al.8 described modeling of the electrophilic addition of water across an alkene in conjunction with performing the reactions in laboratory. The reactions in Graham’s exercise (acid-catalyzed hydration, oxymercuration/demercuration, and hydroboration/ oxidation) are commonly presented in organic chemistry lecture courses as examples of hydration reactions that demonstrate organic chemists’ ability to predict the regiochemical outcome of reactions on the basis of mechanistic ideas and Markovnikov’s rule. Hessley9 described the modeling of the same three reaction mechanisms in a stand-alone exercise designed to explain the observed regiochemistry of these reactions using structure−reactivity relationships. A further extension of the modeling of electrophilic additions to alkenes can be found in an experiment published by Andersh et al.,10 where in addition to using molecular modeling to predict/ explain the regiochemical outcome of the addition of “HOBr” to trans-anethole, the authors included an exploration of the stereochemical outcome of the reaction. In all of these cases, the modeling is used to reinforce what has been learned in lecture about the regiochemistry of electrophilic addition reactions and to help students gain a better understanding of why these reactions proceed as described in their lecture textbooks. An exercise that steps outside of these common themes was published by Horowitz and Schwartz,11 who presented the modeling of reaction mechanisms with which students are not familiar and that result in the production of multiple products. The authors stated that their desire, among other goals, was to “...use molecular modeling to reinforce more general skills such as deducing and drawing reaction mechanisms...”a sentiment that was a driving force in the development of the modeling experiment focusing on atropic acid. More recently, Esselman and Hill12 described the incorporation of molecular modeling across the organic chemistry lab curriculum to support experimentation, helping students gain understanding of their laboratory results and the underlying chemical phenomena behind those results. The current experiment supports that goal as well, even if the students are not actually performing the reaction but rather are trying to explain the results of an experiment from the literature. The desire of instructors to provide students with more guidance in the development of student skills in mechanistic thinking can be seen in a recent article by Flynn

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PRIOR TO THE EXPERIMENT The experiment is designed to be used after students have completed at least a foundational course in organic chemistry. The experiment is short in terms of the modeling, but the questions in the student handout can often take longer than instructors expect. The experiment generally takes 2.5−3 hours to complete. In view of this, the experiment is best used in a lab setting where more time is available. The experiment is designed to be done individually but could certainly be done in pairs. The experiment has been used seven times with a total of 92 students working as individuals, but allowing for discussion of questions with each other and the instructor. Students use their lecture textbooks to review the reaction and mechanism for the electrophilic addition of HX to alkenes, including how one uses arrows to draw the mechanism. They read about Markovnikov’s rule and how it applies to alkene reactions. They also review how to draw resonance structures B

DOI: 10.1021/acs.jchemed.6b00488 J. Chem. Educ. XXXX, XXX, XXX−XXX

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Once this is done, the experiment proceeds with the presentation of the reaction of atropic acid (2-phenylpropenoic acid) with hydrochloric acid to give β-chlorohydratropic acid (3-chloro-2-phenylpropanoic acid), a product that would have to be formed via non-Markovnikov addition to the double bond if atropic acid were to behave like a “normal” alkene. When asked about the structure of the carbocation intermediate that would need to be produced in order to give rise to the observed product, students notice that the non-Markovnikov reaction of the alkene produces a primary carbocation. They note that the primary carbocation intermediate is localized, that is, that they cannot draw any resonance structures that would delocalize the formal positive charge. Students have a difficult time reconciling the fact that this carbocation would need to form in preference to the tertiary benzylic carbocation, which does have resonance that delocalizes the formal positive charge and would normally be expected to be produced in this reaction if atropic acid were to react as a simple alkene. Students are then asked to look closely at the structure of atropic acid for another site of high electron density that might be able to accept the proton from the HCl; the expected answer of the carbonyl oxygen atom or CO π bond usually emerges rather quickly. Students begin the modeling experiment at this time after having been told that as they proceed they will be asked to model all of these cations in an attempt to provide an explanation for the observed regiochemistry in this reaction (Figure 2). Working through the student handout (provided in the Supporting Information), students draw out three different mechanisms related to the cations they model: non-Markovnikov addition of HCl to the alkene via a cation at C3; Markovnikov addition of HCl to the alkene via a cation at C2, which does not result in the formation of the known product of this reaction; and conjugate addition of HCl across the conjugated carbonyl and alkene via an Oprotonated cation (which can also be viewed as a 1,4-addition), with the chloride ion adding to C3. This third possibility involving the O-protonated cation (Figure 2C) would lead to the observed product but can also lead to another, unreported product resulting from attack of the halogen at C1 rather than at C3. The experiment does not address the product arising from attack of the halogen at C1 for reasons outlined in the notes to instructors (provided in the Supporting Information). Having students model the cationic intermediates and utilize the relative stability of these intermediates to predict the product of the reaction presumes that the kinetics of the formation, not the stability of the products, dictates the outcome of this reaction. If this reaction were under thermodynamic control, which is likely given that the reaction is kept warm for 24 h, then the stability of the products would dictate the major product observed. Higher-level DFT calculations support the idea that in this reaction the product reported in the literature resulting from attack of the halogen at C3 is both the kinetic and thermodynamic product. The question then becomes one of the application of Hammond’s postulate to the two possible carbocation intermediates that would lead to the observed product, namely, the C3 cation and the O-protonated cation. The student handout is written in a manner designed to walk students through the logic that could be used by an organic chemist when confronted with an unexpected experimental result such as is observed in this reaction. During the modeling, students are asked to draw mechanisms, resonance structures, resonance hybrids, and LUMO sketches. Energy values are added to a data table and used along with the structures to

and how to use arrows to show how one resonance structure can be converted to the next. Additionally, they review aromaticity and why it is important in a molecule, as well as tautomerization in molecules with carbonyl groups. A review of 1 H NMR interpretation is also suggested. Lastly, students review Hammond’s postulate and how it relates to reaction mechanisms. While it is expected that students have already been instructed in drawing resonance structures and reaction mechanisms, a quick refresher is given as the experiment is introduced. If some guidance from the instructor is given about aromaticity and tautomerization, this experiment could be used after one semester of organic chemistry. Instructors can also include readings and reviews that cover conjugate additions to α,β-unsaturated carbonyl compounds, depending on when the experiment is used in relation to student coverage of that material.

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DURING THE EXPERIMENT Using styrene as a model system, students are first shown an electrophilic addition reaction of HX to an alkene and its mechanism. Styrene is used since it is an asymmetric alkene (and therefore demonstrates Markovnikov addition) and has resonance in the carbocation intermediate. During this part of the experiment, the instructor should ensure that the students remember Markovnikov’s rule as it applies to electrophilic additions to alkenes, how to draw mechanisms in organic chemistry, and how to draw resonance structures (including a resonance hybrid). During this discussion, the instructor should show a picture of the lowest unoccupied molecular orbital (LUMO) of the carbocation intermediate in the addition of HX to styrene in order to demonstrate the correlation of the LUMO and the resonance hybrid, as shown in Figure 1.

Figure 1. LUMO of the carbocation resulting from the addition of HX to styrene from Spartan Student version 6.1.8, showing the correlation of the lobes of the LUMO with the partial positive charges in the resonance hybrid.

A second model system that could also be shown at this time is acrylic acid (propenoic acid), demonstrating how considering this system simply as an alkene would lead to the conclusion that 2-chloropropanoic acid should be the product of the reaction with HCl, whereas the literature states that the product is 3-chloropropanoic acid.4,5 If this second model system is presented, the experiment could then be framed as an exploration of whether atropic acid behaves like styrene (because of resonance in the carbocation intermediate) or like acrylic acid, as well as why both acrylic acid and atropic acid would produce products that do not seem to follow the rules that students have learned to this point in organic chemistry. C

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Figure 2. Resonance hybrids of the three carbocation intermediates modeled in this exercise with the energy differences from the most stable cation based on B97X-D/6-31G* DFT calculations. Students perform PM3 calculations that vary in magnitude from these energy differences. (A) Carbocation intermediate from the Markovnikov 1,2-addition to the alkene, which prior to the experiment students usually predict to be the most stable even though it does not lead to the observed product. This is termed the C2 cation. (B) Carbocation intermediate from the non-Markovnikov 1,2-addition to the alkene, which would lead to the observed product but is usually predicted by students to be less stable than A. This is termed the C3 cation. It should be noted that this energy is obtained only if steps are taken to constrain the geometry to maintain a formal primary carbocation rather than the nonclassical cation expected from a DFT calculation. (C) Carbocation intermediate from the 1,4-addition generated by protonating the carbonyl oxygen atom. This carbocation intermediate leads to the observed product by conjugate addition to C3 and is calculated to be the most stable. This is termed the O-protonated cation.

resonance structures for both the C2- and O-protonated cations. At that point in the handout, only 68% of students generally have the electron-pushing arrows drawn correctly. Later in the handout (page 12), after students have done the modeling, students are again asked to draw out the mechanism for the O-protonated cation and its resonance structures. Now 84% are able to correctly draw four out of four resonance structures for this cation, and 80% can correctly draw the electron-pushing arrows. On page 13, the handout asks students to match 1H NMR spectra to a product with either H or D on C2, and 88% of students can correctly perform this task, even given that there are diastereotopic protons at C3 (although class discussion among students often develops around this topic). Interestingly, when shown an experimental 1 H NMR spectrum of the product on page 15 of the student handout, only 76% of students are able to correctly integrate all of the information to draw a conclusion about the likely mechanism for this reaction. The last question on the student handout is an informal assessment that asks students to describe what they have learned after performing the experiment. Grouping the most common student answers by subject mentioned over seven different sections with a total of 92 students suggests that this experiment can help students increase their comfort level with drawing resonance structures (75%), gives them a greater understanding of how molecular modeling can be used (60%), reinforces how to draw reasonable reaction mechanisms (65%), and provides a simple model showing how one approaches an unexpected result in a stepwise fashion (48%). Given these responses, we believe that this experiment can be a useful tool to help further develop student skills in mechanistic thinking and the use of molecular modeling to probe chemical problems.

answer a series of questions designed to get to the heart of the question: What is a possible mechanism of this reaction given the literature results and the results of the molecular modeling? After examining the possible conjugate addition mechanism, the next series of questions on the student handout involves interpretation of a simple experiment to test the results of the modeling experiment. Students think about the results of running the reaction using DCl instead of HCl and then interpret the simulated 1H NMR spectrum of the possible products.31 If atropic acid reacts as a simple alkene and the 1,2addition mechanism is followed, the incorporation of deuterium on the benzylic carbon in the product should be noticeably different than if the conjugate 1,4-addition mechanism is followed; this would result in different splitting patterns and integrations in the 1H NMR spectrum. In fact, in the related isomerization of maleic to fumaric acid, Horrex32 noted that there was no incorporation of deuterium onto the carbon atoms when the reaction was run using DCl in heavy water. Students are last shown an actual 1H NMR spectrum of the addition of DCl to atropic acid (albeit performed under different reaction conditions) and asked to compare this actual spectrum to the predicted NMR spectra. They find that very little incorporation of deuterium is seen in the spectrum and that the predicted chemical shifts and coupling constants match reasonably well with the experimental values.

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HAZARDS There are no hazards associated with this experiment. CONCLUSION OF THE EXPERIMENT Having gone through the experiment, students will arrive at the conclusion that the likely mechanism of this reaction is a conjugate addition of HCl to the α,β-unsaturated carboxylic acid rather than a simple electrophilic addition across the alkene. By looking at student responses to questions on the student handout for the most recent offerings of this experiment, one can see some clear trends and can utilize the answers as a formative assessment during the experiment to guide discussion. With respect to drawing resonance structures, we note that at the beginning of the exercise (pages 2 and 3), 72% of students are able to correctly identify three out of four

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.6b00488. Detailed notes to instructors (PDF, DOCX) Student handout (PDF, DOCX) Student handout key (PDF, DOCX) D

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Eric D. Helms: 0000-0003-0072-8889 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge Dorothy Voelkers, Jordan O’Malley, Dennis Buckley, and David Johnson for their helpful suggestions and improvements.

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REFERENCES

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DOI: 10.1021/acs.jchemed.6b00488 J. Chem. Educ. XXXX, XXX, XXX−XXX