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Educación química

versión impresa ISSN 0187-893X

Educ. quím vol.27 no.2 Ciudad de México abr. 2016

https://doi.org/10.1016/j.eq.2015.11.006 

¿Cómo se experimenta?

"Green" Suzuki-Miyaura cross-coupling: An exciting mini-project for chemistry undergraduate students

Acoplamiento cruzado "verde" de Suzuki-Miyaura: un mini-proyecto emocionante para estudiantes de pregrado en química

Bruna Pereira Vargasa 

Clarissa Helena Rosaa 

Diego da Silva Rosaa 

Gilber Ricardo Rosaa  * 

aEscola de Química e Alimentos, Universidade Federal do Rio Grande - FURG, Campus Santo Antônio da Patrulha, Rua Barão do Cahy, 125, Cidade Alta, CEP 95500-000, Santo Antônio da Patrulha, RS, Brazil


ABSTRACT

A three-week mini-project is described for an experimental Physical Chemistry or Organic Chemistry course. The activities include synthesis of a biphenyl (4-methoxybiphenyl) via the Suzuki-Miyaura cross-coupling reaction using an adapted domestic microwave oven. The technical skills and concepts that are typically presented in practical chemistry courses are covered, including microwave heating, separation of mixtures, TLC techniques, melting range determination, stoichiometric calculations, and GC-MS techniques.

Keywords Suzuki-Miyaura cross-coupling; Eco-friendly synthesis; Microwave heating; Chemical education

RESUMEN

Un mini-proyecto de 3 semanas se describe en un curso experimental de Fisicoquímica o Química Orgánica. Las actividades incluyen la síntesis de un bifenilo (4-metoxibifenil) a través de la reacción de acoplamiento cruzado de Suzuki-Miyaura usando un horno de microondas doméstico adaptado. Las habilidades técnicas y conceptos que normalmente se presentan en los cursos de química prácticos están cubiertos, incluyendo el calentamiento por microondas, la separación de mezclas, técnicas de TLC, la determinación del intervalo de fusión, cálculos estequiométricos, y las técnicas de GC-MS.

Palabras clave Acoplamiento cruzado de Suzuki-Miyaura; Síntesis sostenible; Calentamiento por microondas; Enseñanza de la química

Introduction

Recent advances in chemistry and specifically the emergence of green chemistry require that students be trained in catalytic organic reactions (Lenardão, Freitag, Dabdoub, Batista, & Silveira, 2003). Microwave heat, a global trend in eco-friendly synthesis, that can be applied in chemistry classes is very efficient and produces excellent results with a short reaction time (Dalmás et al., 2013; Konrath, Piedade, & Eifler-Lima, 2012; Teixeira et al., 2010). Thus, teaching mini-projects that involve more complex organic syntheses (e.g., CC cross-coupling reactions) that are prepared using microwave heat presents a good method for a thorough training in organic chemistry (Aktoudianakis et al., 2008; Soares, Fernandes, Chavarria, & Borges, 2015). Therefore, the use of microwave heat technology in organic synthesis must be included in the training of future professionals.

To provide students with this experience, a three-week experiment (lab period = 3 h/week) is described based on the Suzuki-Miyaura cross-coupling reaction of phenylboronic acid (1) with 4-iodoanisole (2), which is catalyzed by Pd/C, to synthesize 4-methoxybiphenyl (3) via refluxing under air in an adapted domestic microwave oven (Scheme 1; Dalmás et al., 2013).

Scheme 1 Suzuki-Miyaura cross-coupling performed by students. 

The primary goal of this experiment is to introduce students to a research environment by familiarizing them with the scientific literature and detailed laboratory procedures. At the conclusion of the three-week mini-project, students should be more comfortable with synthesizing organic compounds via CC cross-coupling reactions, and they should also be able to identify reaction products using current chromatographic techniques (TLC and GC-MS). They also learn to report their results in a journal-ready format.

Experiment

The students work in groups of three. Prior to the initial laboratory period, students read journal articles related to the experiment (Aktoudianakis et al., 2008; Oliveira et al., 2015; Soares et al., 2015). During week one, a quick introduction to the microwave synthesis technique is provided. Students synthesize compound 3 via the Suzuki-Miyaura cross-coupling reaction that is catalyzed by Pd/C. Phenylboronic acid (1.5 mmol), 4-iodoanisole (1.0 mmol), Pd/C 10 wt.% loading (15 mg, 1.4 mol% of Pd), K2CO3 (2.0 mmol), and 8 mL of dimethylformamide (DMF) are refluxed under air in an adapted domestic microwave oven for an assigned time (30, 45, 50, 60, or 90 min). After the reaction time is complete, the mixture is stored under air at room temperature until the next class.

During week two, the retention factors (Rf) of compounds 1, 2 and 3 (provided by professor) and the reaction mixture are determined using thin layer chromatography (TLC). To determine if the cross-coupling product forms, the students perform the experiment to isolate the 4-methoxybiphenyl from initial reaction mixture.

Week three focuses on the characterization of compound 3. The students collect 4-methoxybiphenyl as white crystals and determine its melting range and mass chromatogram using GC-MS. The detailed procedures are in the Supporting Information.

Results and discussion

The mini-project was implemented with 18 students in 2014 in an upper-division undergraduate course, Physical Chemistry II, Course Agroindustrial Engineering with an emphasis on agrochemistry. The course covered the basic techniques of catalysis that are applied in organic synthesis of bioactive compounds. Additionally, the mini-project was tested with 15 students in 2014 of Technical Course in Chemistry, discipline of Organic Chemistry III, in the Dom Feliciano School (Gravataí - RS, Brazil).

The students found it interesting to use an adapted domestic microwave oven to heat the Suzuki-Miyaura reaction mixture. This apparatus has already been used successfully in NC cross-coupling reactions by our group (Dalmás et al., 2013). The yield ranged from 41% to 92% (Table 1), according to the heating time used. The low yields of compound 3 were associated with variables related to purification and the short reaction time. However, even with unsatisfactory results from the reaction, a fruitful discussion concerning the technical errors can occur. The reported melting range of the pure 4-methoxybiphenyl is 81-83.5 °C (Rosa, Rosa, Rominger, Dupont, & Monteiro, 2006). Each student group reported melting points that were within this range (Table 1). Moreover, the students analyzed the mass chromatogram obtained for compound 3 using the GC-MS technique. Representative data from a student group is provided in the Instructor's Notes in Supporting Information.

Table 1 The results obtained for each group during the mini-project. 

Group Affiliation Time (min) Melting range (°C) Yield (%)
1 Dom Feliciano 30 74-76 61
2 FURG 30 81-82 41
3 Dom Feliciano 45 84-86 60
4 FURG 45 81-83 53
5 Dom Feliciano 50 82-85 52
6 FURG 50 86-88 57
7 Dom Feliciano 60 81-84 74
8 FURG 60 86-89 79
9 FURG 60 81-82 83
10 Dom Feliciano 90 84-85 78
11 FURG 90 82-85 92

a Suzuki-Miyaura cross-coupling conditions: 4-iodoanisole (1.0 mmol), phenylboronic acid (1.5 mmol), Pd/C (15 mg, 1.4 mol% of Pd), K2CO3 (2.0 mmol), DMF (8 mL), refluxed under air in the adapted domestic microwave oven to produce the isolated yields.

The students found it interesting to use an adapted domestic microwave oven to heat the Suzuki-Miyaura reaction mixture. This apparatus has already been used successfully in NC cross-coupling reactions by our group (Dalmás et al., 2013). The yield ranged from 41% to 92% (Table 1), according to the heating time used. The low yields of compound 3 were associated with variables related to purification and the short reaction time. However, even with unsatisfactory results from the reaction, a fruitful discussion concerning the technical errors can occur. The reported melting range of the pure 4-methoxybiphenyl is 81-83.5 °C (Rosa, Rosa, Rominger, Dupont, & Monteiro, 2006). Each student group reported melting points that were within this range (Table 1). Moreover, the students analyzed the mass chromatogram obtained for compound 3 using the GC-MS technique. Representative data from a student group is provided in the Instructor's Notes in Supporting Information.

The longer reaction times resulted in higher yields. Approximately 90 min was necessary to fully convert the reagents to the cross-coupling product (previously tested). Group 1 obtained a higher than expected yield after 30 min. For this time, the conversion is low (∼45%), and we believe the product contains traces of compound 2 (mp 50-53 °C) with 3. There were no major differences in the yield obtained by the students in the technical course (Dom Feliciano) as opposed to those in the undergraduate (FURG) course for the reaction times of 45-60 min. However, the data from the undergraduates were more consistent (see Fig. 1). This shows the flexibility of the mini-project, which can be applied to both levels of education. For 90 min, group 10 likely lost the mass of the isolated product during the procedure.

Figure 1 Comparison of results obtained in the mini-project for the different courses. 

These results were explained using the classic catalytic cycle for the Suzuki-Miyaura cross-coupling reaction (only the FURG students, Fig. 2). The adopted catalytic system is eco-friendly because of the use of microwave heat and phosphine-free conditions, which are global trends in modern organic synthesis. Other Pd sources (commercial salts) can also be tested as catalysts in this CC cross-coupling reaction (Zim, Monteiro, & Dupont, 2000).

Figure 2 Catalytic cycle of the Suzuki-Miyaura cross-coupling reaction (Oliveira et al., 2015). 

Conclusion

This three-week mini-project introduced students to a modern organic synthesis process. This study was designed as a low-cost, practical class that promotes the use of materials and reagents available in laboratories with limited resources. Starting with basic information, students prepared compound 3 via the Suzuki-Miyaura cross-coupling reaction, purified it via crystallization, determined its melting range and obtained a mass chromatogram to confirm its purity. Additionally, the students used a common procedure in modern organic chemistry laboratories. To conclude this mini-project, the students provided an explanation for the phenomenon in a laboratory report (in manuscript format).

The pedagogical objectives proposed for this mini-project were fully achieved. The sequence of the related activities motivated and effectively engaged all students, creating a cooperative spirit between the workgroups. The students participating in similar activities exhibited outstanding performance in the research groups.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

This work was supported by grants from CNPq (# 404601/2013-8) and FAPERGS (# 14/0339-9) (Brazil).

References

Aktoudianakis et al., 2008 Aktoudianakis E, Chan E, Edward A.R, Jarosz I, Lee V, Mui L, et al. "Greening up" the Suzuki reaction. Journal of Chemical Education. 2008; 85:555-7 [ Links ]

Dalmás et al., 2013 Dalmás M, Moura N.F, Rosa G.R, Ferreira C.L, Santos J.A.O, Bolzan T.K, et al. Mini-project for teaching experimental organic chemistry based on NC cross-coupling promoted by microwave. Química Nova. 2013; 36:1464-7 [ Links ]

Konrath et al., 2012 Konrath E.L, Piedade M, Eifler-Lima V.L. Microwave-assisted phenytoin synthesis: Proposed practical class for undergraduate students. Química Nova. 2012; 35:1887-90 [ Links ]

Lenardão et al., 2003 Lenardão E.J, Freitag R.A, Dabdoub M.J, Batista A.C.F, Silveira C.C. Green chemistry - The 12 principles of green chemistry and it insertion in the teach and research activities. Química Nova. 2003; 26:123-9 [ Links ]

Oliveira et al., 2015 Oliveira D.G.M, Rosa C.H, Vargas B.P, Rosa D.S, Silveira M.V, de Moura N.F, et al. Introducing undergraduates to research using a Suzuki-Miyaura cross-coupling organic chemistry miniproject. Journal of Chemical Education. 2015; 92:1217-20 [ Links ]

Rosa et al., 2006 Rosa G.R, Rosa C.H, Rominger F, Dupont J, Monteiro A.L. A mixed NCP pincer palladacycle as catalyst precursor for the coupling of aryl halides with aryl boronic acids. Inorganica Chimica Acta. 2006; 359:1947-54 [ Links ]

Soares et al., 2015 Soares P, Fernandes C, Chavarria D, Borges F. Microwave-assisted synthesis of 5-phenyl-2-hydroxyacetophenone derivatives by a green Suzuki coupling reaction. Journal of Chemical Education. 2015; 92:575-8 [ Links ]

Teixeira et al., 2010 Teixeira E.F, dos Santos A.P.B, Bastos R.S, Pinto A.C, Kümmerle A.E, Coelho R.R. The use of domestic microwave oven in experimental classes of organic chemistry: Salicylaldehyde nitration. Química Nova. 2010; 33:1603-6 [ Links ]

Zim et al., 2000 Zim D, Monteiro A.L, Dupont J. PdCl2(SEt2)2 and Pd(OAc)2: Simple and efficient catalyst precursors for the Suzuki cross-coupling reaction. Tetrahedron Letters. 2000; 41:8199-202 [ Links ]

Peer Review under the responsibility of Universidad Nacional Autónoma de México.

Appendix A. Supplementary data

Student Handout (procedures for the synthesis and characterization of 4-methoxybiphenyl) and Instructor's Notes. This material is available via the Internet in PDF file format, free of charge.

Supplementary data associated with this article can be found, in the online version, at doi: 10.1016/j.eq.2015.11.006.

Received: August 03, 2015; Accepted: October 20, 2015

Corresponding author. gilberrosa@furg.br

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