Reply to “Pericyclic or Pseudopericyclic? The Case of an Allylic

Letter pubs.acs.org/jchemeduc

Reply to “Pericyclic or Pseudopericyclic? The Case of an Allylic Transposition in the Synthesis of a Saccharin Derivative” Custódia S. C. Fonseca* Department of Chemistry and Pharmacy, Faculty of Sciences and Technology, University of Algarve, 8005-139 Faro, Portugal ABSTRACT: Sigmatropic rearrangement is one of the main classes of pericyclic reactions, which does not necessarily mean that these rearrangements have a pericyclic mechanism. The allylic saccharin derivative O-cinnamylsaccharin can isomerize into N-cinnamylsaccharin in the polar solvent system toluene/ triethylamine in a reaction time of 2 h at 110 °C. The mechanism of this reaction is pseudopericyclic and may be elucidated using theoretical calculations. However, this is not an easy topic, and therefore, it should be taught in phases and using the three main resources: theoretical classes, laboratory experiments and computer experiments. Here I aim to explain this perspective.

KEYWORDS: Upper-Division Undergraduate, Graduate Education/Research, Organic Chemistry, Theoretical Chemistry

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INTRODUCTION Sigmatropic rearrangement is a topic in pericyclic reactions that belongs to the programs of disciplines such as Organic Chemistry II or Advanced Organic Chemistry in undergraduate or Master courses in Chemistry, Physical Chemistry, or Pharmacy. This Journal published a paper describing a sequential synthesis of N-cinnamylsaccharin in which the last step was a [1,3] sigmatropic rearrangement.1 That paper was a subject of a recently published Letter criticizing the introduction of a sigmatropic rearrangement in the undergraduate curriculum and the allegedly inaccurate explanation of its mechanism.2 The present letter explains the reasons why the [1,3] sigmatropic rearrangement experiment was proposed as a laboratory session for undergraduate organic students and discusses the mechanism of this reaction.

undergraduate curriculum. Probably the most popular books are the ones by Wade,3 Klein,4 Clayden,5 and Carey;6 all of these have a chapter on pericyclic reactions that includes sigmatropic rearrangements. Therefore, the inclusion of a rearrangement experiment in a second-semester organic chemistry course looks quite logical to us. The [1,3] rearrangement of O-cinnamylsaccharin is easy to set up, supervise, and grade by the teacher; besides, it illustrates an unusual organic reaction and may be very useful in explaining what a sigmatropic rearrangement is, leaving aside the details of the mechanism, the Woodward−Hoffmann rules, classification of the mechanism as pericyclic or pseudopericyclic, etc., which can be taught at the theoretical lectures instead. The main idea was to keep all of the theoretical description that supports the laboratory experiment to the necessary minimum in the laboratory protocol, with the topic explained and discussed in the theoretical lectures in the discipline. Additionally, I provided an adequate bibliography for those students or teachers who would like to get deeper into the subject.

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[1,3] SIGMATROPIC REARRANGEMENT AS A LABORATORY EXPERIMENT FOR UNDERGRADUATE STUDENTS The presentation of organic chemistry to undergraduate students has never been an easy task. It is surprising that the questions of what should be taught to undergraduates, how should be taught, and the order and methods for presenting the material had attracted little attention. The textbooks chosen usually influence the way the discipline is taught, both in the topics covered and the way they are presented, and therefore, I can use popular textbooks as a guide to how courses should be taught. Nowadays there are a huge number of videos on platforms such as YouTube; in a more organized way, there are free organic courses in Khan Academy and Coursera that cover most of the organic chemistry topics included in the © XXXX American Chemical Society and Division of Chemical Education, Inc.

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THEORETICAL CALCULATIONS VERSUS EXPERIMENTAL CONDITIONS The experimental work described in ref 1 involves as the last step a [1,3] sigmatropic rearrangement of O-cinnamylsaccharin to N-cinnamylsaccharin using toluene/trimethylamine as a polar solvent system and a reaction time of 2 h at 110 °C. The mechanism of this reaction was studied in the papers listed in Received: May 31, 2017 Revised: June 26, 2017

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DOI: 10.1021/acs.jchemed.7b00373 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Letter

Scheme 1. Reaction Mechanism for the [1,3] Sigmatropic Rearrangement of O-Cinnamylsaccharin into N-Cinnamylsaccharin

Notes

ref 7 and was also discussed in ref 1. These referenced papers use NMR experiments, X-ray crystallography, and theoretical calculations with Gaussian software and the CAChe WorkSystem. The theoretical calculations complement the experimental studies, pointing to a concerted pathway with an ionic transition state, as the rearrangement occurs faster with better yields in polar media such as toluene/trimethylamine, with the transition state being less demanding given the negative ionic character of the nitrogen atom and the steric hindrance induced by the bulky SO2 group. Another obvious conclusion is that the reaction considered has a pseudopericyclic mechanism, as presented in Scheme 1. The Letter by Tantillo2 merely reports theoretical calculations, which can help to clarify the pseudopericyclic mechanism of the reaction and the Woodward−Hoffmann rules, while ignoring as it does the solvent polarity due to the presence of trimethylamine in the reaction medium and therefore disregarding the interaction energy between the ions in the pair.

The author declares no competing financial interest.

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CONCLUSIONS It is important to introduce concepts that may be later developed or complemented in more advanced disciplines in the same area of knowledge in order to ensure continuity of education. Pericyclic reactions form a topic where this approach may be fruitfully used, and thus, the experimental work described in ref 1, with the third synthesis introducing sigmatropic rearrangement for undergraduate students, may be complemented by the theoretical calculations described in Tantillo’s letter for use in postgraduate (advanced) disciplines in Organic Chemistry. Thus, pericyclic reactions are an excellent example where laboratory work may be advantageously complemented by theoretical calculations.

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REFERENCES

(1) Fonseca, C. S. C. Saccharin Derivative Synthesis via [1,3] Thermal Sigmatropic Rearrangement: A Multistep Organic Chemistry Experiment for Undergraduate Students. J. Chem. Educ. 2016, 93, 1781−1784. (2) Hare, S. R.; Tantillo, D. J. Pericyclic or Pseudopericyclic? The Case of an Allylic Transposition in the Synthesis of a Saccharin Derivative. J. Chem. Educ. 2017, DOI: 10.1021/acs.jchemed.6b00825. (3) Wade, L. G., Jr.; Simek, W. J. Organic Chemistry, 9th ed.; Pearson Education: Harlow, England, 2016; pp 752−782. (4) Klein, D. Organic Chemistry, 2nd ed.; Wiley: West Sussex, England, 2014; pp 701−751. (5) Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed.; Oxford University Press: Oxford, England, 2012; pp 877−970. (6) Carey, F. A.; Sundberg, J. R. Advanced Organic Chemistry, 5th ed.; Springer: New York, 2007; pp 605−663. (7) (a) Cristiano, M. L. S.; Brigas, A. F.; Johnstone, R. A. W.; Loureiro, R. M. S.; Pena, P. C. A. Thermal Rearrangement of 3Allyloxy-1,2-benzisothiazole 1,1-dioxides: an unusual inversion of products of sigmatropic [3,3] − shift to give the [1,3] − isomers. J. Chem. Res., Synop. 1999, No. 12, 704−705. (b) Araújo, N. C. P.; Barroca, P. M. M.; Bickley, J. F.; Brigas, A. F.; Cristiano, M. L. S.; Johnstone, R. A. W.; Loureiro, R. M. S.; Pena, P. C. A. Structural Effects on Sigmatropic Shifts in Heteroaromatic Allyl Ethers. J. Chem. Soc., Perkin Trans. 1 2002, 1213−1219. (c) Cabral, L. I. L; Maria, T. M. R.; Martelo, L.; Eusébio, M. E. S.; Cristiano, M. L. S.; Fausto, R. The Thermal Sigmatropic Isomerization of Pseudosaccharyl Crotyl Ether. Tetrahedron 2013, 69 (2), 810−815. (d) Gómez-Zavaglia, A.; Kaczor, A.; Almeida, R.; Cristiano, M. L. S.; Eusébio, M. E. S.; Maria, T. M. R.; Mobili, P.; Fausto, R. Thermally Induced Sigmatropic Isomerization of Pseudosaccharyl Allylic Ether. J. Phys. Chem. A 2009, 113 (15), 3517− 3522. (e) Duarte, L.; Reva, I.; Cristiano, M. L. S.; Fausto, R. Photoisomerization of Saccharin. J. Org. Chem. 2013, 78 (7), 3271− 3275.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Custódia S. C. Fonseca: 0000-0002-2480-3364 B

DOI: 10.1021/acs.jchemed.7b00373 J. Chem. Educ. XXXX, XXX, XXX−XXX