Laboratory Experiment pubs.acs.org/jchemeduc
Cite This: J. Chem. Educ. XXXX, XXX, XXX−XXX
Regioselectivity in Hetero Diels−Alder Reactions Carla Grosso,† Marta Liber,‡ Amadeu F. Brigas,‡ Teresa M. V. D. Pinho e Melo,† and Américo Lemos*,†,‡ †
CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal CIQA and Departamento de Química e Farmácia, Faculdade de Ciências e Tecnologia, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro, Portugal
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S Supporting Information *
ABSTRACT: Regioselectivity in hetero Diels−Alder reactions can be observed in a simple reaction between a nonsymmetrical heterodiene and an unsymmetrical heterodienophile. A 9 h and easy to implement laboratory experiment is described, in which students can observe the regioselectivity of inverse “electron-demand” hetero Diels−Alder reactions of an azoalkene with furan or 2,3dihydrofuran acting as dienophile. This experiment combines synthesis, structural analysis (IR spectroscopy and NMR spectroscopy), and dry- and vacuum-flash isolation methods.
KEYWORDS: Upper-Division Undergraduate, Organic Chemistry, Hands-On Learning/Manipulatives, Heterocycles, NMR Spectroscopy, IR Spectroscopy
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1,4,5,6-Tetrahydropyridazine derivatives 9 (Scheme 2), resulting from the Diels−Alder reaction of azoalkenes with electronrich alkenes, are usually obtained with high regio- and stereoselectivity, as predicted by frontier molecular orbital (FMO) interactions, or by simple resonance theory. In these HOMOdienophile−LUMOdiene controlled reactions the major (or exclusive) regioisomer results from the interaction of the terminal conjugated atom of the electron-rich alkene or heterocycle bearing the higher HOMO coefficient, or higher electron density, with the terminal conjugated atom of the azoalkene bearing the LUMO higher orbital coefficient, or major electron deficiency (electrophilicity) (Scheme 2). These laboratory cycloaddition reactions, under very mild conditions, aim at the practical demonstration of the regioselectivity of hetero Diels−Alder reactions between a nonsymmetrical azoalkene with two (nonsymmetrical) electron-rich dienophiles exemplifying and clearly showing, this way, the theoretical predictions illustrated in Scheme 2.
he Diels−Alder reaction is a [4π + 2π] cycloaddition of a conjugated diene and a dienophile (alkene or alkyne). When one or both of these molecules carry a heteroatom, the reaction is called a hetero Diels−Alder reaction and constitutes one of the most powerful methods for the construction of 6membered-ring heterocycles. The Diels−Alder reaction involving a nonsymmetrical diene/heterodiene and an unsymmetrical dienophile/heterodienophile may produce a mixture of regioisomers, in accordance with their relative direction or orientation of approach at the transition state. While several experiments are available in organic chemistry to demonstrate the basic concepts of a Diels−Alder reaction, simple and sufficiently easy to implement experiments (within a laboratory classroom/educational context) involving hetero Diels−Alder reactions are very scarce.1 The past several decades confirmed conjugated azoalkenes (also called 1,2-diaza-1,3-dienes or DDs; e.g., Scheme 1, heterodienes 2 or 5), mostly obtained via dehydrohalogenation of the respective α-halo-hydrazones 1 or 4 (Scheme 1), as powerful intermediates in the synthesis of an impressive number of new heterocyclic systems either through hetero Diels−Alder cycloaddition or 1,4-conjugate addition reactions. Examples of these reactions are shown in Scheme 1.2,3 Azoalkenes carrying one, or more often, two electronwithdrawing groups, possess a strong electrophilic character. Therefore, their cycloadditions are predominantly with electron-rich double bonds and electron-rich heterocycles in a Diels−Alder process with “inverse ‘electron-demand’”. © XXXX American Chemical Society and Division of Chemical Education, Inc.
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EXPERIMENT OVERVIEW These laboratory experiments (Scheme 3) have been carried out over more than 6 different academic years by third-year undergraduate students within an advanced organic chemistry course divided into 3 sessions of approximately 3 h, Received: December 5, 2017 Revised: September 4, 2018
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DOI: 10.1021/acs.jchemed.7b00933 J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Laboratory Experiment
Scheme 1. Examples of 1,4-Conjugated Addition and Hetero Diels−Alder Cycloadditions
Scheme 2. Regioselectivity in Inverse “Electron-Demand” Hetero Diels−Alder Reaction
First Session
Ethyl bromopyruvate t-butoxycarbonyl hydrazone, 10, is prepared efficiently from the reaction of commercially available ethyl bromopyruvate and tert-butyl carbazate in a mixture of diethyl ether/pentanes with a reaction time of only 20 min.4 The target hydrazone precipitates from the reaction media and is isolated by filtration. The melting point of the product is measured and the infrared (IR) spectrum recorded. At the end of this session, hydrazone 10, furan 12, and sodium carbonate in dichloromethane are left stirring overnight to afford 1-tertbutyl 3-ethyl-1,4,4a,7a-tetrahydrofuro[3,2-c]pyridazinedicarboxylate, 13. Second Session
The second session involves the isolation of 135 and characterization by melting point and IR spectroscopy. A sample is prepared, and the 1H and 13C NMR spectra are recorded. At the end of this session, hydrazone 10, 2,3dihydrofuran 14, and sodium carbonate in dichloromethane are left stirring overnight leading to the synthesis of 1-tertbutyl-3-ethyl 1,4,4a,5,6,7a-hexahydrofuro[2,3-c]pyridazinedicarboxylate, 15. Third Session
This session involves the isolation and characterization of 15. The melting point of the product is measured, and samples are prepared to record its IR and 1H and 13C NMR spectra.
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HAZARDS All experiments should be carried out in a fume hood, and students must wear proper safety equipment such as protective clothing, gloves, and safety glasses. All of the materials in the experiments should be handled with care and used within a fume hood. tert-Butylcarbazate [CAS 870-46-2] is a flammable solid, harmful if swallowed or in contact with skin. Ethyl bromopyruvate [CAS 70-23-5] causes severe skin burns and irritation and serious eye damage/ irritation and may cause respiratory irritation. Furan [CAS
respectively. Each class has 16 students working in a group of 2; likewise, each laboratory class had 8 different groups (working in 8 slightly different projects, see notes for instructors in Supporting Information, p S14) with one instructor per class. B
DOI: 10.1021/acs.jchemed.7b00933 J. Chem. Educ. XXXX, XXX, XXX−XXX
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Scheme 3. Synthesis of 13 and 15 via Inverse “Electron-Demand” Diels−Alder Reactions, Rationalized by Resonance (Top) and FMO (Bottom)
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110-00-9] is a highly flammable liquid and vapor. When uninhibited, it forms explosive peroxides on exposure to air. The vapors are narcotic. Inhalation may involve both reversible and irreversible changes and high toxixity by ingestion or skin absorption. Anhydrous sodium carbonate [CAS 497-19-8] may cause eye irritation. It is harmful if swallowed or inhaled and causes irritation to skin and the respiratory tract. 2,3Dihydrofuran [CAS 1191-99-7] is highly flammable liquid. It causes serious eye damage/irritation. Diethyl ether [CAS 6029-7] is an extremely flammable liquid, and vapors may be an explosion hazard. It is harmful if swallowed, causes mild skin irritation, serious eye damage, and respiratory irritation. It has narcotic effects and is suspected of damaging fertility or the fetus. Petroleum ether (bp 40−60 °C) [CAS 64742-49-0] is highly flammable, is an irritant, is dangerous for the environment, and may cause lung damage if swallowed. Dichloromethane [CAS 75-09-2] causes damage to the brain and central nervous system. It is also a probable carcinogen, is hazardous via skin or eye contact and inhalation, and may cause skin burns. Potassium bromide [CAS 7758-02-3] causes severe eye irritation and also is a (possible) carcinogen suspect. Silica gel [CAS 112926-00-8] may be harmful if inhaled or swallowed. It may cause respiratory tract irritation. Chloroform-d [CAS 865-49-6] is harmful if swallowed and causes skin and eye irritation. It is toxic if inhaled, is suspected of causing cancer and damage to the fetus, and causes damage to organs. Within our experience, cycloadducts 13 and 15 are harmless under standard safety laboratory manipulation conditions.
RESULTS AND DISCUSSION
Spectral Analysis
IR Spectroscopy. IR spectroscopy will be a valuable tool since the failure or success of the transformation of the hydrazone into a cycloadduct may be immediately inferred. The N−H absorption band clearly observed in the IR spectrum of the starting hydrazone 10 will be absent in the IR spectrum of products 13 and 15. Cycloadduct 13 may be partially converted into the corresponding open chain hydrazone, if left standing at room temperature or above for a long time, due to the aromatization of the furan ring. In this case, the N−H absorption band of this derivative may be observed (see Scheme 4). NMR Spectroscopy. The analysis of the 1H NMR spectra (see Supporting Information) of compounds 13 and 15 allows their unambiguous structural assignment and the establishment of the regiochemistry observed in the studied cycloadditions Scheme 4. Eventual Rearomatization of Furan Ring at Room Temperature (or Above)
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DOI: 10.1021/acs.jchemed.7b00933 J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Laboratory Experiment
Figure 1. Representative parts of 1H NMR spectra of cycloadducts 13 (top) and 15 (bottom), from students’ sample data.
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(Figure 1). In the case of cycloadduct 15, proton H-7a is observed as a doublet at 5.59 ppm, due to the coupling with H4a. On the other hand, in the 1H NMR spectrum of cycloadduct 13, proton H-7a is observed at a much lower chemical shift, within a complex multiplet and unresolved signals between 5.11 and 5.24 ppm.
Corresponding Author
*E-mail:
[email protected]. ORCID
Amadeu F. Brigas: 0000-0003-4875-4453 Teresa M. V. D. Pinho e Melo: 0000-0003-3256-4954 Américo Lemos: 0000-0001-9588-4555
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CONCLUSIONS The theoretical prediction of the regioselectivity observed in (hetero) Diels−Alder reactions is illustrated and demonstrated in these laboratory experiments. The C-4 orbital of the azoalkene, carrying the highest coefficient or electrophilic density, overlaps with the C-5 of furan carrying the highest coefficient or electron (or nucleophilic) density, while N-1 interacts with C-4 of furan. With 2,3-dihydro-furan the atom carrying the highest electron density will be C-4, and consequently, an apparent reverse regiochemistry is observed. These reactions, carried out at room temperature and under very mild conditions, involving simple manipulations and easy isolation and handling procedures may constitute an interesting combination of an theoretical prediction and its experimental demonstration with simple and uncomplicated implementation.
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AUTHOR INFORMATION
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is dedicated to Dr. Thomas L. Gilchrist by the occasion of its 80th birthday. We acknowledge the Nuclear Magnetic Resonance Laboratory of the Coimbra Chemistry Center, University of Coimbra, for obtaining the NMR spectroscopic data. Coimbra Chemistry Centre (CQC) is supported by the Portuguese Agency for Scientific Research, the Fundaçaõ para a Ciência e a Tecnologia (FCT), through project no. POCI-01-0145-FEDER-007630, cofunded by COMPETE2020-UE.
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ASSOCIATED CONTENT
REFERENCES
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S Supporting Information *
The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.7b00933. Detailed experimental procedures, flash vacuum chromatography description, instructions for students, and detailed spectroscopic data with respective IR and 1H and 13C NMR spectra (PDF, DOCX) D
DOI: 10.1021/acs.jchemed.7b00933 J. Chem. Educ. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.jchemed.7b00933 J. Chem. Educ. XXXX, XXX, XXX−XXX
