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Cite This: J. Chem. Educ. XXXX, XXX, XXX−XXX

Shedding Blue Light on the Undergraduate Laboratory: An Easy-toAssemble LED Photoreactor for Aromatization of a 1,4Dihydropyridine David A. Contreras-Cruz,*,†,‡ Margarita Cantú-Reyes,‡ Juan M. García-Sánchez,† Daniel Peña-Ortíz,§ Miguel A. Sánchez-Carmona,§ and Luis D. Miranda*,‡ †

Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México, 09230, Mexico Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán, Ciudad de México, 04510, Mexico § Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM, Universidad Autónoma del Estado de México, Carretera Toluca-Atlacomulco Km 14.5, Toluca, MEX, 50200, Mexico

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‡

S Supporting Information *

ABSTRACT: A photochemical reactor was tested in an undergraduate teaching laboratory through the environmentally friendly aromatization of a 1,4-dihydropyridine, successfully using air as an oxidant, organic dye fluorescein as a photosensitizer, and sodium carbonate as a base. This experiment allowed students to be taught key concepts of photochemistry, organic photoredox catalysis, and green chemistry for the first time. Herein, we describe the making of the simple, yet robust, high-intensity blue LED photoreactor. The durable device was constructed with materials acquired at a hardware store and electronics shop.

KEYWORDS: Second-Year Undergraduate, Organic Chemistry, Hands-On Learning/Manipulatives, Free Radicals, Green Chemistry, Heterocycles, Laboratory Equipment/Apparatus, Photochemistry

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strips, since these devices are capable of producing intense light fluxes without losing brightness. There are several recently published photoreactor designs which use ultraviolet4 and visible light sources.5 In this Journal, some of these designs have been specially built for laboratory exercises in chemistry teaching.4a−j,5a,b The most notable example is McMillan’s LED photoreactor,6 which is highly efficient in several photoredox catalysis reactions and was manufactured with the purpose of standardizing these photochemical processes. However, the construction of such a device involves the utilization of a 3D printer and a Raspberry Pi controller, which prevents the general public from building it. Therefore, an easy-to-build LED photoreactor design is highly desirable. Our reactor design employs CREE XT-E blue LEDs as a light source, as shown in Figure 1. These were chosen for providing higher luminous flux compared to commercial LED strips and other high-power LED models. Each CREE XT-E blue LED produces typically luminous fluxes of 256 lm, an

ver the past decade, photoredox catalysis has become a promising and powerful tool for synthetic chemists, making some reactions which were once considered impossible, feasible. The use of visible light to promote organic reactions is a fast-growing technique, and new useful applications will continue to be found in the fields of total synthesis and synthetic methodologies.1 However, despite expanding interest in the research community, there have been few attempts to incorporate photoredox catalysis experiments into undergraduate laboratory curriculum2 because such practices are considered problematic and expensive. With the intention of encouraging teachers to include this type of experiments in their courses, an easy-to-assemble blue LED photoreactor was developed. Light-emitting diodes (LEDs) are monochromatic. They are more efficient, reliable, durable, and cheaper sources of illumination than conventional light sources such as bulb lamps, fluorescent lights, and “sun” lamps and are even brighter than direct sunlight.3 Thanks to these advantages, LED devices are widely used in photochemistry today. Although LED strips have traditionally been used, they provide relatively low light intensity and lose their shine intensity over time due to excessive heating. High-power LEDs are an alternative to LED © XXXX American Chemical Society and Division of Chemical Education, Inc.

Received: January 1, 2019 Revised: July 9, 2019

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DOI: 10.1021/acs.jchemed.8b01026 J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Laboratory Experiment

Figure 1. (a) Labeled view of the dismounted apparatus with components. (b) Photograph of the blue light reactor while it is on.

amount of illumination that allows for greater penetration of photons into the reaction vessel. CREE XT-E LEDs emit a narrow interval that ranges from 450 to 452 nm. An arrangement of six CREE XT-E blue LEDs (1536 lm) mounted on the inside of a reflective aluminum box (8.9 × 8.9 × 9.6 cm3) allows vials to be irradiated from multiple directions. The reason for mounting LEDs on aluminum sheets is to dissipate the heat that they generate as well as to extend their service life. During operation, the apparatus is cooled with the help of a fan placed at the bottom, in such a way that the temperature inside the reactor does not exceed 28 °C. The fan serves as a firm base and fits the aluminum box well. Construction cost was approximately $45 USD, so it is an accessible device for a teaching laboratory, with the advantage that anyone with a minimum knowledge of electronics can build it. However, in some cases, the assembly of the photoreactor can be delegated to a dedicated machine or electronic shop. The estimated construction time for the device is 18 h. For the electrical connection, a 12 V DC (2 A) power supply is connected parallel to two series of LEDs and the fan, as shown in Figure 2. Each series of LEDs consists of three CREE XT-E LEDs attached to a ceramic resistor. The purpose of the resistors is to protect the LEDs from excess electrical current, thus extending their service life (for an explanation of the stepby-step assembly, see the Supporting Information, p S19). Special care must be taken for the negative pole of the power source to be connected to the resistors, and one must verify that the LEDs are connected in the correct polarity or they will not light up. In this work, the device was tested in the aerobic photoaromatization of a 1,4-dihydropyridine (DHP). The reaction involved the formation of reactive oxygen species through successive single electron transfers (SET). The

Figure 2. Circuit diagram of the device (photoreactor).

aromatization of 1,4-DHPs has been extensively studied. However, many of the methodologies involve the use of strong, toxic oxidants, the requirement of harsh conditions, and the need of an excess of oxidants.7 Recently, more efficient and environmentally benign reagents that perform this conversion have come into the spotlight.8 The 1,4-DHP core was chosen because of its relevant biological activity. A number of 1,4-DHPs, such as nifedipine and nimodipine, are heterocyclic drugs of choice in the treatment of hypertension and angina pectoris.9 The B




nifedipine, nimodipine, and 1,4-DHP used in this experiment are oxidized in the liver by cytochrome P-450 to produce the corresponding pyridine derivative.10 On the other hand, during the industrial synthesis of several 1,4-DHPs, pyridine derivatives are commonly obtained as the main impurities.11 This could affect the effectiveness, safety, and quality of drugs available on the market,12 hence the importance of becoming familiar with this type of photochemical transformation.

Scheme 1. Photoaromatization of the 1,4-DHP Derivative

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EXPERIMENTAL METHODS In order to test the photoreactor utility, a modified procedure for the aromatization of a 1,4-DHP to a pyridine derivative was executed.13 Experiments were performed by second-year undergraduate students of a Bachelor’s degree in Biological and Pharmaceutical Chemistry. This experiment was the fifth of seven, performed in a laboratory course focused on synthetic organic chemistry in which there was no experiment covering the topic of photochemistry. The photochemistry experiment took place with two groups in different periods, using a 5 h laboratory session per period with two teaching assistants, so that closer monitoring could be provided. A total of 22 students participated; each student did the experiment only once. The pedagogical goals of this experiment were achieved through the following strategy: (1) Students were asked to read an online article explaining how light can cause chemical changes.14 (2) A prelab class was given as a verbal introduction to key concepts in photoredox catalysis and green chemistry principles, followed by a brief discussion of the expected signals of 1,4-DHP and pyridine derivative shown in NMR and IR analysis. (3) Students performed the experiment following the method provided by the teaching assistants. (4) Teaching assistants applied a questionnaire to the students in a postlaboratory session, and the student’s answers were analyzed to evaluate the learning outcomes. The learning objectives pursued in this experiment were the following: • Understanding the basic principles of photoredox catalysis, as well as its potential for application in industry and academy • Being aware of the 12 principles of green chemistry • Observing the fluorescence phenomenon using uranine as a photosensitizer • Being able to obtain and interpret the IR and NMR spectra of the product obtained, as well as the starting material

uranine formed in situ was an excellent photosensitizer capable of absorbing the radiation emitted by blue LEDs (λex = 460 nm). The green hue of uranine solution is typical and intensifies when irradiated (λem = 515 nm). Additionally, the high water solubility of uranine and sodium carbonate allowed them to be readily extracted using a water−dichloromethane system. Atmospheric oxygen could be employed as an oxidant because it is abundant and free. In a typical experiment, each student took an average of just 7 min to prepare the reaction. They mixed the substances a day earlier. A methanol−water mixture was added as a solvent, and the mixture was irradiated overnight while stirring in an open atmosphere. Reactions were performed in conventional test tubes, with no need of special sample holders. Purification of the pyridine derivative was performed the next day, taking place in an average time of 20 min. The aromatization product was obtained as a white, crystalline solid and was characterized by TLC, 1H NMR, 13C NMR, and IR spectroscopic analyses.

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HAZARDS It is important to wear yellow safety glasses to avoid retinal damage while the reactor is on.16 A lab coat and gloves must be worn. Additionally, a transparent yellow acrylic sheet can be used to cover the device and avoid glare. UV light can damage the eyes and skin. Fluorescein and sodium carbonate are irritants. 1,4-DHP is harmful if swallowed and causes skin irritation upon contact. Pyridine derivative is harmful if swallowed and causes skin irritation upon contact. Hexane is a neurotoxin, volatile, and flammable. Ethyl acetate is flammable. Methanol is toxic and flammable. Dichloromethane is toxic. Deuterated chloroform is a carcinogen. Vanillin stain causes eye and skin irritation upon contact; do not inhale intentionally.

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Photoaromatization of 1,4-Dihydropyridine Using Visible Light

RESULTS AND DISCUSSION We present the assembly of the first blue LED batch photoreactor with a cooling system, applied to a teaching laboratory. Most importantly, it is safe for students to handle. A major advantage over other similar devices is that, if an electrical part of the appliance burns out, it can be easily replaced. This simple design can be adapted on top of magnetic stirrers to obtain vigorous stirring, using a magnetic bar inside round-bottomed flasks, vials, and test tubes. The photoreactor can accommodate a maximum of six test tubes (15 mL, 16 × 125 mm2 each). Since the temperature inside the

All reagents are commercially available except Hantzsch 1,4DHP, which was prepared in accordance with a reported method.15 Fluorescein is an organic photoredox catalyst that provides several advantages over iridium and ruthenium complexes, such as a lack of toxicity and greater availability in teaching laboratories. In our proposal, fluorescein free acid was used due to its low cost and the ease of being converted to uranine in the presence of sodium carbonate (Scheme 1). Sodium carbonate was the base, chosen for being inexpensive, safe, and able to deprotonate fluorescein and 1,4-DHP. The C




reactor is only 28 °C during operation, low-boiling solvents can be used; this also prevents undesired reactions caused by excessive heating. With that in mind, the aluminum body, fan, and heat sinks play a fundamental role. The LED arrangement inside the irradiation chamber allows photons to penetrate the reaction vessel from several directions, which increases the possibility of exciting the photoredox catalyst. Additionally, the reflective capacity of aluminum allows photons to reenter the reaction mixture. In principle, the same design can be used with commercially available high-power LEDs of other wavelengths. It is worth noting that the device described herein has been used for the synthesis of functionalized indoles through photoredox catalysis,17 obtaining yields similar to those previously reported, for which its usefulness in a research laboratory is proven. The photoreactor can remain in continuous operation for several days, which is convenient for long experiments. Since photochemistry is not an issue commonly addressed in undergraduate laboratory courses, this experiment caused great expectation and interest among the students. With this background, it was possible to experimentally show the phenomenon of fluorescence to the students as well to take the opportunity to explain how a single electron transfer mechanism occurs (for a detailed description of the reaction mechanism, see the Supporting Information, p S4). One of the advantages of this experimental procedure was that the reagents used were solid, which made it easier for students to handle and place them into test tubes. A remarkable fact was that, during the addition of the methanol−water mixture to the reaction tube, the solution acquired a fluorescent green glow that students associated with the deprotonation of fluorescein. The base, oxidant, and solvents used herein were safe and easily handled by students. The waste generated was not toxic to the environment. In this sense, the use of the organic photoredox catalyst, base, and solvents in this practice complies with several principles of green chemistry.18 If the drawback of reaction scalability would be present in this batch photoreactor design, a continuous flow chemistry system could easily be adapted to the device for solving this issue.5b Monitoring progress of the reaction through TLC provided a simple “spot-to-spot” profile (hexanes−ethyl acetate, 75:25 v/v), in which the 1,4-DHP was the most polar “spot” (Rf = 0.22) followed by the product “spot” (Rf = 0.4). The use of vanillin staining is recommended, since the fact that both compounds stained in different colors made it easier for students to identify them. In this batch photoaromatization, yields obtained by students were high (70−97%), and no secondary products were present in the reaction mixture even after prolonged irradiation times (17−26 h). Total conversion of the 1,4-DHP was achieved after 17 h. In a control experiment with no photosensitizer, only traces of pyridine derivative were obtained after 24 h, showing students the importance of the photoredox catalyst in this reaction. In order to demonstrate the superiority of the blue LED photoreactor against conventional lighting, two photoaromatization experiments under identical conditions were performed by the students using a 25 W CFL bulb (for a description of the CFL setup, see the Supporting Information, p S15). In these cases, the starting material was consumed after 48 h and the product yields were lower (40−54%).

After purification, students were able to obtain the NMR and IR spectra of the pyridine derivative and 1,4-DHP. The 1H NMR (CDCl3) spectrum of the pyridine derivative showed the disappearance of N−H and benzylic signals at 6.16 and 4.99 ppm, respectively, which had previously been present in the 1H NMR spectrum of 1,4-DHP. The 13C NMR (CDCl3) spectrum of the pyridine derivative also exhibited the seven expected aromatic carbons at 155.5, 146.2, 136.7, 128.5, 128.2, 128.1, and 127.0 ppm. NMR peaks illustrated that the pyridine derivative was highly pure. The IR spectrum of the pyridine derivative showed the disappearance of the N−H signal at 3340 cm−1, which had previously been present in the IR spectrum, of 1,4-DHP. Students were able to identify characteristic pyridine derivative and 1,4-DHP signals from NMR and IR spectra (see the Supporting Information, pp S24−S30). To evaluate the knowledge acquired from this experiment, students were given a questionnaire. More than 70% were able to correctly answer questions such as “Which 1,4-DHP and pyridine derivative signals are to be expected in the NMR spectra?”, “What would happen if less than 1 equiv of base was used?”, “Could a compact fluorescent lamp (CFL), a sodium lamp, or a filament bulb be used as light sources in this reaction?”, “Explain why vigorous stirring is called for in this experiment”, and “Explain why, after liquid−liquid extraction, uranine remained in the aqueous phase while pyridine derivative remained in the organic phase” (for the complete questionnaire, see the Supporting Information, pp S6−S12). It was concluded that students understood both the importance of vigorous stirring and the role of the photoredox catalyst in the reaction, based on correct responses in the questionnaire and laboratory report. The pedagogical goals were assessed by the success of the students in performing the reactions (e.g., in the form of high yield and purity of the pyridine derivative) and from the positive results of their questionnaires. Some of the most notable aspects of the experiment were as follows: • The photoaromatization experiment was performed in two sessions. The first involved the preparation of the reaction in an average time of 7 min, followed by overnight irradiation. The next day, isolation of the product took an average time of 20 min. • Thanks to the simplicity of both the experimental procedure and the purification step, students obtained a satisfactory yield of high-purity pyridine derivative. • The students mentioned that this experiment was their first contact with the subject of photochemistry and that they were enthused to know they had applied their laboratory skills in a cutting-edge field such as that of organic photoredox catalysis. • Students discussed the use of visible light as a “clean reagent”, which was a novelty for them, since they are more accustomed to thermal reactions than those promoted by light. • Although the reaction mechanism proposed in this experiment was more complex than most of those previously learned by second-year undergraduate students, this experiment allowed them to reaffirm free radical chemistry concepts as well to learn new redox reaction concepts such as single electron transfer. D



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• In this experiment, a product very similar to the impurities obtained during the production of antihypertensive drugsnifedipine and nimodipinewas synthesized. The identification of such impurities is key for the pharmaceutical industry, as it helps to ensure the quality of the drugs on the market.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.8b01026. Experimental procedure of photoaromatization with a proposed mechanism, notes to the teacher, instructions for assembling the reactor, and spectra of compounds (PDF, DOCX)

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REFERENCES

(1) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363. (b) Narayanam, J. M. R.; Stephenson, C. R. J. Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 2011, 40, 102−113. (c) Matsui, J. K.; Lang, S. B.; Heitz, D. R.; Molander, G. A. Photoredox-Mediated Routes to Radicals: The value of Catalytic Radical Generation in Synthetic Methods Development. ACS Catal. 2017, 7, 2563−2575. (d) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116, 10075−10166. (2) (a) Chen, S. Let There Be Light: Hypothesis-Driven Investigation of Ligand Effects in Photoredox Catalysis for the Undergraduate Organic Chemistry Laboratory. J. Chem. Educ. 2018, 95, 872−875. (b) Rapp, T. L.; Phillips, S. R.; Dmochowski, I. J. Kinetics and Photochemistry of Ruthenium Bisbipyridine Diacetonitrile Complexes: An Interdisciplinary Inorganic and Physical Chemistry Laboratory Exercise. J. Chem. Educ. 2016, 93, 2101− 2105. (c) Watts, R. J. Ruthenium polypyridyls: A case study. J. Chem. Educ. 1983, 60, 834−842. (3) (a) Schubert, E. F.; Kim, J. K. Solid-State Light Sources Getting Smart. Science 2005, 308, 1274−1278. (b) Savage, N. MIT Technology Review. http://www.technologyreview.com/s/400801/ leds-light-the-future (accessed July 2019). (4) (a) Aung, T.; Liberko, C. A. Bringing Photochemistry to the Masses: A Simple, Effective, and Inexpensive Photoreactor, Right Out of the Box. J. Chem. Educ. 2014, 91, 939−942. (b) Stefanov, B. I.; Lebrun, D.; Mattsson, A.; Granqvist, C. G.; Ö sterlund, L. Demonstrating Online Monitoring of Air Polluttant Photodegradation in a 3D Printed Gas-Phase Photocatalysis Reactor. J. Chem. Educ. 2015, 92, 678−682. (c) Chen, X.; Halasz, S. M.; Giles, E. C.; Mankus, J. V.; Johnson, J. C.; Burda, C. A Simple Parallel Photochemical Reactor for Photodecomposition Studies. J. Chem. Educ. 2006, 83, 265−267. (d) Xiong, Q.; Luo, M.; Bao, X.; Deng, Y.; Qin, S.; Pu, X. Using Photocatalytic Oxidation and Analytic Techniques To Remediate Lab Wastewater Containing Methanol. J. Chem. Educ. 2018, 95, 131−135. (e) Ibanez, J. G.; Mena-Brito, R.; FregosoInfante, A. Laboratory Experiments on the Electrochemical Remediation of the Environment. Part 8. Microscale Simultaneous Photocatalysis. J. Chem. Educ. 2005, 82, 1549−1551. (f) Gravelle, S.; Langham, B.; Geisbrecht, B. V. Photocatalysis A Laboratory Experiment for an Integrated Physical-Chemistry-Instrumental Analysis Course. J. Chem. Educ. 2003, 80, 911−913. (g) Zhang, R.; Liu, S.; Yuan, H.; Xiao, D.; Choi, M. M. F. Nanosized TiO2 for Photocatalytic Water Splitting Studied by Oxygen Sensor and Data Logger. J. Chem. Educ. 2012, 89, 1319−1322. (h) Taber, D. F.; Paquette, C. M. Photochemistry Is Back in the Undergraduate Organic Laboratory. J. Chem. Educ. 2013, 90, 1105−1106. (i) Thompson, M. P.; Agger, J.; Wong, L. S. Paternò- Büchi Reaction as a Demonstration of Chemical Kinetics and Synthetic Photochemistry Using a Light Emitting Diode Apparatus. J. Chem. Educ. 2015, 92, 1716−1720. (j) Hoffmann, H.; Tausch, M. W. Low-Cost Equipment for Photochemical Reactions. J. Chem. Educ. 2018, 95, 2289−2292. (k) Chen, D. H.; Ye, X.; Li, K. Oxidation of PCE with a UV LED Photocatalytic Reactor. Chem. Eng. Technol. 2005, 28, 95− 97. (l) Jamali, A.; Vanraes, R.; Hanselaer, P.; Van Gerven, T. A batch LED reactor for the photocatalytic degradation of phenol. Chem. Eng. Process. 2013, 71, 43−50. (m) Casado, C.; Timmers, R.; Sergejevs, A.; Clarke, C. T.; Allsopp, D. W. E.; Bowen, C. R.; Van Grieken, R.; Marugán, J. Design and validation of a LED-based high intensity photocatalytic reactor for quantifying activity measurements. Chem. Eng. J. 2017, 327, 1043−1055. (n) Ghosh, J. P.; Langford, C. H.; Achari, G. Characterization of an LED Based Photoreactor to Degrade 4-Chlorophenol in an Aqueous Medium Using Coumarin (C-343) Sensitized TiO2. J. Phys. Chem. A 2008, 112, 10310−10314. (5) (a) Tatarko, M.; Tricker, J.; Andrzejewski, K.; Bumpus, J. A.; Rhoads, H. Remediation of Water Contaminated with an Azo Dye: An Undergraduate Laboratory Experiment Utilizing an Inexpensive Photocatalytic Reactor. J. Chem. Educ. 1999, 76, 1680−1683.

CONCLUSION An inexpensive and efficient blue LED photoreactor was successfully tested in the metal-free photoaromatization reaction of a 1,4-DHP. The ease of construction, low cost, and robustness of this device should encourage teachers to include photosensitized oxidation laboratory experiments in undergraduate chemistry programs. Moreover, we consider that our contribution showed students the importance of organic photoredox catalysis as a swiftly growing field.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

David A. Contreras-Cruz: 0000-0002-9765-7097 Margarita Cantú-Reyes: 0000-0001-7756-6617 Juan M. García-Sánchez: 0000-0001-7944-1009 Daniel Peña-Ortíz: 0000-0001-7447-977X Miguel A. Sánchez-Carmona: 0000-0002-5249-1943 Luis D. Miranda: 0000-0003-0342-8160 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS D.A.C.-C. thanks CONACyT for a Ph.D. scholarship (grant 271165) and PAPIME-UNAM (grant PE206115) for financial support. The authors would like to thank the undergraduate students (Scarlet Cordero, David Carmona, Johanna Colorado, ́ Gerardo Martinez, Brandon Sánchez, Mariá López, Mario ́ Castañoń , Enrique Becerril, Jaime Martinez, Thaliá Vázquez, Cynthia Orta, Fernando Aguayo, Rubi ́ Ortega, Nadia San Miguel, Brenda Garduño, Cinthya Olguin, Diana Román, Mariá de Jesús Hernández, Brenda Á ngeles, Moisés Carreón, ́ Alison Ramirez, and Oscar Cruz) who carried out the photoaromatization experiments. The authors would like to thank Raquel Retana-Ugalde for her help in implementing this experiment in SFMP I course and Fabián Cuétara-Guadarrama for his helpful comments. We also thank Roció Patiño-Maya and Lourdes Castillo-Granada for technical support. The figures were created by Gerardo Camacho and used with permission. The electronic circuit scheme was drawn in the open-source software Fritzing, ver. 0.8.2b.19 E




(b) Santandrea, J.; Kairouz, V.; Collins, S. K. Continous Flow Science in an Undergraduate Teaching Laboratory: Photocatalytic Thiol-Ene Reaction Using Visible Light. J. Chem. Educ. 2018, 95, 1073−1077. (c) Zalesskiy, S. S.; Shlapakov, N. S.; Ananikov, V. P. Visible light mediated metal-free thiol-yne click reaction. Chem. Sci. 2016, 7, 6740−6745. (d) Lee, D. S.; Amara, Z.; Clark, C. A.; Xu, Z.; Kakimpa, B.; Morvan, H. P.; Pickering, S. J.; Poliakoff, M.; George, M. W. Continuous Photo-Oxidation in a Vortex Reactor: Efficient Operations Using Air Drawn from the Laboratory. Org. Process Res. Dev. 2017, 21, 1042−1050. (e) Clark, C. A.; Lee, D. S.; Pickering, S. J.; Poliakoff, M.; George, M. W. A Simple and Versatile Reactor for Photochemistry. Org. Process Res. Dev. 2016, 20, 1792−1798. (f) Gonçalves, R. S.; Rabello, B. R.; César, G. B.; Pereira, P. C. S.; Ribeiro, M. A. S.; Meurer, E. C.; Hioka, N.; Nakamura, C. V.; Bruschi, M. L.; Caetano, W. An Efficient Multigram Synthesis of Hypericin Improved by a Lower Power LED Based Photoreactor. Org. Process Res. Dev. 2017, 21, 2025−2031. (6) Le, C. C.; Wismer, M. K.; Shi, Z.; Zhang, R.; Conway, D. V.; Li, G.; Vachal, P.; Davies, I. W.; MacMillan, D. W. C. A General SmallScale Reactor To Enable Standardization and Acceleration of Photocatalytic Reactions. ACS Cent. Sci. 2017, 3, 647−653. (7) (a) Kumar, P.; Kumar, A. An Expeditious Oxidative Aromatization of Hantzsch 1,4-Dihydropyridines to Pyridines Using Cetyltrimethylammonium Peroxodisulfate: A Phase Transferring Oxidant. Bull. Korean Chem. Soc. 2010, 31, 2299−2303. (b) Memarian, H. R.; Sadeghi, M. M.; Momeni, A. R. Aromatization of Hantzsch 1,4Dihydropyridines Using Barium Manganate. Synth. Commun. 2006, 31, 2241−2244. (c) Pfister, J. R. Rapid, High-Yield Oxidation of Hantzsch-Type 1,4-Dihydropyridines with Ceric Ammonium Nitrate. Synthesis 1990, 1990, 689−690. (8) (a) Chen, Z. Y.; Zhang, W. Oxidative aromatization of Hantzsch 1,4-dihydropyridines by aqueous hydrogen peroxide-acetic acid. Chin. Chem. Lett. 2007, 18, 1443−1446. (b) Yadav, J. S.; Subba Reddy, B. V.; Sabitha, G.; Kiran Kumar Reddy, G. S. Aromatization of Hantzsch 1,4-dihydropyridines with I2-MeOH. Synthesis 2000, 2000, 1532− 1534. (c) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Oxidative Aromatization of 1,3,5-Trisubstituted Pyrazolines and Hantzsch 1,4Dihydropyridines by Pd/C in Acetic Acid. Org. Lett. 2002, 4, 3955− 3957. (9) (a) Varon, J.; Marik, P. E. Clinical review: The management of hypertensive crises. Crit. Care. 2003, 7, 374−384. (b) Janis, R. A.; Triggle, D. J. New developments in calcium ion channel antagonists. J. Med. Chem. 1983, 26, 775−785. (10) Boecker, R. H.; Guengerich, F. P. Oxidation of 4-aryl- and 4alkyl-substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)-1,4-dihydropyridines by human liver microsomes and immunochemical evidence for the involvement of a form of cytochrome P-450. J. Med. Chem. 1986, 29, 1596−1603. (11) (a) Pötter, H.; Hülm, M. Assay of nifedipine and its by- and degradation products in the drug substance and dragees by liquid chromatography on formamide-saturated silica gel columns. J. Pharm. Biomed. Anal. 1988, 6, 115−119. (b) Barmpalexis, P.; Kanaze, F. I.; Georgarakis, E. Developing and optimizing a validated isocratic reversed-phase high-performance liquid chromatography separation of nimodipine and impurities in tablets using experimental design methodology. J. Pharm. Biomed. Anal. 2009, 49, 1192−1202. (c) Sadana, G. S.; Ghogare, A. B. Quantitative Proton Magnetic Resonance Spectroscopic Determination of Nifedipine and Its Photodecomposition Products from Pharmaceutical Preparations. J. Pharm. Sci. 1991, 80, 895−898. (12) (a) Ha, L. D.; Nguyen, T. T. D.; Le, T. M. Synthesis and establishment of Amlodipine impurity G reference standard. J. Appl. Pharm. Sci. 2017, 7, 105−110. (b) Galan-Rodríguez, C.; GonzálezÁ lvarez, J.; Valls-Remolí, M. Method development and validation study for quantitative determination of nifedipine and related substances by ultra-high-performance liquid chromatography. Biomed. Chromatogr. 2015, 29, 233−239. (c) European Directorate for the Quality Control of Medicines. European Pharmacopoeia, 7th ed.; European Directorate for the Quality Control of Medicines: France,

2006; pp 2571−2572. (d) European Directorate for the Quality Control of Medicines. European Pharmacopoeia, 7th ed.; European Directorate for the Quality Control of Medicines: France, 2006; pp 2578−2579. (13) Wei, X.; Wang, L.; Jia, W.; Du, S.; Wu, L.; Liu, Q. Metal-freemediated oxidation aromatization of 1,4-dihydropyridines to pyridines using visible light and air. Chin. J. Chem. 2014, 32, 1245−1250. (14) Contreras-Cruz, D. A. Cienciorama. http://www.cienciorama. unam.mx/a/pdf/569_cienciorama.pdf (accessed July 2019). (15) Wang, C.; Lu, Z. Intermolecular [2 + 2] Cycloaddition of 1,4Dihydropiridines with Olefins via Energy Transfer. Org. Lett. 2017, 19, 5888−5891. (16) Behar-Cohen, F.; Martinsons, C.; Viénot, F.; Zissis, G.; BarlierSalsi, A.; Cesarini, J. P.; Enouf, O.; Garcia, M.; Picaud, S.; Attia, D. Light-emitting diodes (LED) for domestic lighting: Any risks for the eye? Prog. Retinal Eye Res. 2011, 30, 239−257. (17) (a) Swift, E. C.; Williams, T. M.; Stephenson, C. R. J. Intermolecular Photocatalytic C-H Functionalization of Electron-Rich Heterocycles with Tertiary Alkyl Halides. Synlett 2016, 27, 754−758. (b) Furst, L.; Matsuura, B. S.; Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. R. J. Visible Light-Mediated Intermolecular C-H Functionalization of Electron-Rich Heterocycles with Malonates. Org. Lett. 2010, 12, 3104−3107. (18) (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998. (b) Hjeresen, D. L.; Boese, J. M.; Schutt, D. L. Green Chemistry and Education. J. Chem. Educ. 2000, 77, 1543−1547. (c) Kirchhoff, M. M. Topics in Green Chemistry. J. Chem. Educ. 2001, 78, 1577. (19) Fritzing Web site. http://fritzing.org/home/ (accessed July 2019).

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