Introducing the Concept of Green Synthesis in the Undergraduate

Communication pubs.acs.org/jchemeduc

Introducing the Concept of Green Synthesis in the Undergraduate Laboratory: Two-Step Synthesis of 4‑Bromoacetanilide from Aniline Ratul Biswas and Anuradha Mukherjee* Undergraduate Chemistry, Indian Institute of Science, Bangalore-560012, India S Supporting Information *

ABSTRACT: Incorporation of green chemistry techniques in undergraduate (UG) laboratories has a great demand. The challenge is to select and modify the known fundamental reactions in a greener way to implement into UG laboratories. A practical, two-step synthesis of 4-bromoacetanilide from aniline through a greener approach is described. Design of the synthetic route is based on the fundamental concepts of green chemistry. It can be adapted in most of the UG laboratories, including those with limited facilities. In the first step, aniline is converted to acetanilide using Zn dust/Fe powder−acetic acid instead of conventional acetic anhydride. In the second step, acetanilide is brominated using ceric ammonium nitrate−KBr combination in ethanolic−aqueous medium instead of bromine. The overall concept of modification could be useful to teach students about the concept of green chemistry, functional group protection, aromatic electrophilic substitution, and laboratory techniques such as reaction setup, isolation, purification, and product analysis. KEYWORDS: Second-Year Undergraduate, Organic Chemistry, Safety/Hazards, Hands-On Learning/Manipulatives, Qualitative Analysis, Electrophilic Substitution, Green Chemistry, Laboratory Equipment/Apparatus

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the hazardous liquid bromine such as pyridinium tribromide5 and potassium bromate (KBrO3) in the presence of hydrogen bromide (HBr) and acetic acid.6 These reagents generate elemental bromine in situ as the reaction progresses. In 2016, the preparation of acetanilide was described using trimethyl ortho-ester (TMOA) with amine hydrochloride7 where students have observed two major products (imidate and amide) by TLC and identified them by GC−MS. This “TLC−GC−MS” approach serves as excellent training for students as an alternative to traditional N-acetylation, but it is suitable when students have access to use a GC−MS facility in a basic organic laboratory course.8 In 2012, a multistep synthesis of 4bromoacetanilide from aniline was reported9 using acetic anhydride for acetylation of amine followed by treatment with sodium hypochlorite (NaOCl)−sodium bromide (NaBr) for electrophilic aromatic10 bromination in an acetic acid (AcOH)−water medium. However, isolation of product from the reaction mixture (acetic acid−water) is a tedious job as it requires neutralization of acetic acid and destruction of excess NaOCl. The present experiment describes N-acetylation of aniline using easily available Zn dust−AcOH and bromination using CAN−KBr (Scheme 1) replacing acetic anhydride and liquid

INTRODUCTION Green Chemistry with its 12 principles1 modifies the conventional reactions that have been used for decades to synthesize organic chemical substances. This green approach increases the efficiency of synthetic methods by reducing the steps of the synthesis and minimizing toxic solvents and byproducts. Hence, this concept is adopted both in research laboratories and industrial production units. Incorporation of this concept thus has a great importance in undergraduate (UG) laboratories.2 Synthesis of 4-bromoacetanilide from aniline is a common experiment in UG laboratories. Conventional methods of performing the same often present a potential hazard for inexperienced undergraduate students. Synthesis of acetanilide from aniline is commonly performed using acetic anhydride,3a−c which is one of the controlled substances3d in India because of its use in the acetylation of morphine to obtain heroin. Liquid bromine is also considered a hazardous reagent, and it generates toxic and corrosive hydrogen bromide (an environmental pollutant) during electrophilic aromatic bromination.3e In addition to this, handling bromine itself is a safety concern. To overcome these problems, several alternative methods have been developed for acetylation of amines and bromination of arenes. N-Acylation using various reagents like N,N′-carbonyldiimidazole4a (CDI), Zn dust with acetyl chloride,4b and solid supported4c,d reagents are reported in the literature. Several green reagents for bromination have been developed to replace © XXXX American Chemical Society and Division of Chemical Education, Inc.

Received: October 7, 2016 Revised: July 12, 2017

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DOI: 10.1021/acs.jchemed.6b00749 J. Chem. Educ. XXXX, XXX, XXX−XXX

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Scheme 1. Synthesis of Acetanilide and 4-Bromoacetanilde

addition of CAN solution, the reaction mixture was poured into ice cold water to get a white precipitate that was filtered and recrystallized from ethanol. Students recorded the mp and the IR spectrum of the product. See SI for experimental details.

bromine or NaOCl−NaBr, respectively. This new, modified synthetic route can be considered greener and safer for UG laboratories since use of hazardous chemicals is minimized and a complicated isolation process is also avoided. The experimental design is inspired by two different reports11,12 and modified suitably for undergraduate students.

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HAZARDS Eye protection, lab coats, and gloves should be worn throughout the course of the reaction. Students should perform their reactions in a well-ventilated fume hood. Acetic acid is corrosive and flammable. It can cause burns. Aniline is harmful if inhaled. Zn dust is stable in dry air but reacts vigorously with water. N-Acetyl products are hazardous in case of eye contact (irritant) and skin contact (irritant). If ingested, seek medical advice immediately. Ceric ammonium nitrate causes respiratory, skin, and eye irritation. The hazards of all the reagents and products are included in the SI.

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CHEMICALS AND EQUIPMENT All chemicals used were of standard grade obtained from commercial suppliers and used without further purification. Melting points were measured using a Thermocal10, Analab Scientific Instruments Pvt Ltd. (ISO 9001:2000 certified). Infrared spectral data were collected using a Bruker Alpha FTIR spectrometer. 1H and 13C NMR spectra were collected on Zeol 500 MHz spectrometer using CDCl3 as a solvent. Tetramethylsilane (TMS; δ = 0.00 ppm) served as an internal standard for NMR spectroscopy.

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RESULTS AND DISCUSSION Initially, N-acetylation and bromination reactions were implemented as an individual experiment in the laboratory sessions of the Basic Organic Chemistry course (UC-206) for two consecutive years. Later, both the steps were combined and successfully implemented by more than 100 second-year undergraduates in the next two years. The students worked in pairs for two lab periods. Each day ∼30 students performed this experiment. In the first lab period, students performed Nacetylation. During the laboratory session, out of 100 students 16 were assigned to perform Fe-mediated N-acetylation to experience the superiority of Zn over Fe (Table 1).

EXPERIMENTAL OVERVIEW Before implementation of this experiment in a UG laboratory course, both steps were optimized by an instructor. Step 1 was performed with different amounts (%) of Zn dust to optimize the reaction conditions. In this optimized protocol, the mole ratios of aniline, Zn, and acetic acid were taken in the ratio 1:0.3:5. With this approach in mind, the N-acetylation step was attempted with Fe powder13 instead of Zn, which afforded relatively poor yields (72% yield using Zn dust and 15−21% yield using Fe powder by an experienced chemist). During a prelab meeting, these studies and results were shared with the students which helped them to understand the concept of research behind the process of reaction optimization. The background information was also provided to the students on the basis of a few reported articles6,7,9,12 to explain the benefits of the new methods. After the prelab discussion, students were brought to the laboratory to introduce them to basic laboratory techniques, mentioned in Supporting Information (SI). Students added aniline in the suspension of the Zn dust− acetic acid mixture (Scheme 1, step 1, path A) or the Fe powder−acetic acid mixture (Scheme 1, step 1, path B) and heated at 100−110 °C for 2 h. While the 2 h reflux was in progress, a group discussion was arranged to discuss the topic of green chemistry.2 After 2 h, the reaction mixture was poured onto ice and stirred vigorously to obtain a white solid that was purified by recrystallization from hot water. Product formation was confirmed by qualitative test (−NHCOCH3 group), melting point (mp) determination, and IR spectrum. In the second week, students performed a bromination (Scheme 1, step 2). To a mixture of acetanilide and potassium bromide in ethanol was added an aqueous solution of CAN. After complete

Table 1. Yield Comparison: Zn Dust versu Fe Powder synthetic routes

yield (isolated by students)

Zn dust−AcOH Fe powder−AcOH

40−60% 15%

In the reported procedure,11 a catalytic amount of zinc acetate was used in the presence of AcOH under microwave irradiation, whereas, in the modified procedure, expensive zinc acetate was replaced with easily available inexpensive Zn dust and AcOH to generate zinc acetate in situ. Keeping in mind the basic facilities of UG laboratories, microwave irradiation was avoided with implementation of a reflux technique. The product was obtained in 72% yield by an experienced chemist. Most of the students (∼74% students) isolated product in the range 40−60%. Students (∼12%) isolated product below 20% due to losing the compound during the filtration and recrystallization process. Detailed results are summarized in Table S4, SI. B

DOI: 10.1021/acs.jchemed.6b00749 J. Chem. Educ. XXXX, XXX, XXX−XXX

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On the next day of the lab, 4-bromoacetanilide was synthesized and isolated as a white solid by simple filtration after pouring the reaction mixture in ice cold water. This reaction was attractive for students because they visualized the color changes from colorless to red to yellow to white indicative of each individual step: formation of bromine (red), reaction with CAN and KBr (red to yellow), and consumption of bromine by acetanilide (orange-yellow to white). The reaction is so rapid that within 10−15 min students can observe the formation of a white solid. Isolation of the para isomer was confirmed by melting point determination as well as 1H and 13 C NMR spectra. In the reported method,12 LiBr and CAN were used as brominating agents in acetonitrile solvent under a nitrogen atmosphere. The product was isolated by ether extraction and purified by column chromatography. In terms of advantages, reagents used for the modified synthetic route are safer, easy to handle, and inexpensive (e.g., LiBr is hygroscopic and more expensive than KBr); also, ethanol−water is nontoxic unlike acetonitrile. In another report, bromination9 was performed using NaOCl−NaBr in acetic acid−water medium. 4-Bromoacetanilide was isolated after addition of sodium thiosulfate and sodium hydroxide, to quench excess NaOCl and neutralize AcOH to recover the product, respectively, thus making the isolation of product tedious. In this modified method, isolation of product was simple and straightforward. The maximum yield obtained by an experienced chemist was 71%. A majority of students (86%) isolated product in 50−60% yield (see Table S5, SI). After isolation of both the products, in the present case, students characterized the product of step 1 by a simple functional group test and both step 1 and step 2 products by mp determination which was compared with the reported data (Table S6, SI). Individual groups recorded IR spectrum of their purified products (representative student data are mentioned in Figures S3 and S6, SI) and assigned the important peaks (amine group, 3275−3481 cm−1; amide, 1631−1676 cm−1 as characteristic peaks). IR spectrum of 4-bromoacetanilide did not show any significant difference from acetanilide. Representative 1H and 13C NMR data of both the products were shared with them to illustrate the characteristic peaks (representative student data are shown in Figures S1, S2, S4 and S5, SI). 13 C NMR spectrum of synthesized 4bromoacetanilide was compared with the reported 2-bromo and 3-bromoacetanilide to demonstrate how the 13C NMR spectrum can be an important tool to determine the isomers. The four aromatic carbons in the 13C NMR spectrum of 4bromoacetanilide emphasize the importance of 13C NMR spectroscopy in characterizing the product. After compiling the data, all the students participated in a discussion guided by the instructor. There was an open discussion about the green chemistry principles and greenness of this particular experiment. Students calculated mass intensity (MI) and atom economy (AE) (principles 1 and 2) of both the reactions N-acetylation and bromination (Table 2). See SI for calculation of AE% and MI. Both processes used less hazardous chemicals, which follows principle 3. It also follows principle 5 as it avoids quenching with separation agents (Na2S2O3/NaOH) by adopting a simple filtration technique. Though the N-acylation reaction (step 1) is not an energetically efficient process, the bromination (step 2) follows principle 6. Overall, the classroom discussion on the experiment revealed that many factors play a role in the

Table 2. AE% and MI for Acetanilide and 4Bromoacetanilide Synthesis synthetic routes acetanilide synthesis using Zn dust and AcOH 4-bromoacetanilide synthesis using CAN + KBr

atom economy (AE%) 62% 26.68%

mass intensity (MI) 4.37 20.78

development of greener methodologies, and there remains much scope for improvement of greening the UG laboratory. An assessment of the achievement of pedagogical goals was obtained by conducting an examination after completion of the UC-206 course. Grades are awarded to students on the basis of the level of performance. Performance was assessed in two categories (i) skill of experiment and (ii) response in viva voce. For the first one, grades were awarded on the basis of the learner’s ability to demonstrate their learning outcomes like stoichiometric calculation, reaction setup, record of experimental details, yield calculation, characterization of the product by qualitative analysis, and interpretation of important peaks from supplied spectral data. Understanding of the relevant chemical principles was assessed by the second following conclusion of experiments. A graphical presentation of students’ assessment result is shown in Figure 1. The assessment result

Figure 1. Graphical presentaion of students’ assessment data.

was analyzed to determine if students’ learning outcomes were met. Out of 100 students, 3 students secured 100% marks, and 80 nine students got marks in the range 60−99%. For details see Table S7, SI.

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SUMMARY Greening the undergraduate laboratory is an active area of research. With an aim to create awareness about green and sustainable chemistry among a new generation of students, a modified two-step synthesis of the organic reaction, aniline to 4-bromoacetanilide, was described here. A simple experimental setup with readily available, safer reagents makes this experiment perfectly suitable for both sophisticated and unsophisticated undergraduate laboratories. Moreover, it fulfills pedagogical goals like (i) learning laboratory techniques, (ii) multistep synthesis, (iii) green chemistry concept, (iv) methodology development using various reagents, (v) reaction optimization with a systematic and logical approach to solve a problem in the laboratory, and finally (vi) application of modern spectroscopy techniques like IR, 1H NMR, and 13C NMR for elucidating molecular structure. Thus, this experiment is a perfect combination of fundamental organic reactions, multistep synthesis, and green chemistry that can be adaptable C

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2017). (e) Wright, O. L.; Mura, L. E. The Bromination of Anthracene. J. Chem. Educ. 1966, 43, 150. (4) (a) Chikkulapalli, A.; Aavula, S. K.; Mona, NP. R.; Karthikeyan, C.; Vinodh Kumar, C. H.; Sulur, G. M.; Sumathi, S. Convenient Nacetylation of amines in N, N-dimethylacetamide with N, Ncarbonyldiimidazole. Tetrahedron Lett. 2015, 56, 3799−3803. (b) Pasha, M. A.; Reddy, M. B. M.; Manjula, K. Zinc dust: An extremely active and reusable catalyst in acylation of phenols, thiophenol, amines and alcohol in a solvent-free system. Eur. J. Chem. 2010, 1, 385−387. (c) Paul, S.; Nanda, P.; Gupta, R.; Loupy, A. Ac2O−Py/basic alumina as a versatile reagent for acetylations in solvent-free conditions under microwave irradiation. Tetrahedron Lett. 2002, 43, 4261−4265. (d) Yadav, V. K.; Babu, G. K.; Mittal, M. KFAl2O3 is an efficient solid support reagent for the acetylation of amines, alcohols and phenols. Impeding effect of solvent on the reaction rate. Tetrahedron 2001, 57, 7047−7051. (5) (a) Merker, P. C.; Vona, J. A. The use of pyridinium bromide perbromide for brominations. J. Chem. Educ. 1949, 26, 613−614. (b) McKenzie, L. C.; Huffman, L. M.; Hutchison, J. E. The Evolution of a Green Chemistry Laboratory Experiment: Greener Brominations of Stilbene. J. Chem. Educ. 2005, 82, 306−310. (c) Daley, J. M.; Landolt, R. G. A Substitute for “Bromine in Carbon Tetrachloride. J. Chem. Educ. 2005, 82, 120−121. (6) Schatz, P. F. Bromination of acetanilide. J. Chem. Educ. 1996, 73, 267. (7) Saba, S.; Ciaccio, J. A. Reaction of Orthoesters with Amine Hydrochlorides: An Introductory Organic Lab Experiment Combining Synthesis, Spectral Analysis, and Mechanistic Discovery. J. Chem. Educ. 2016, 93, 945−948. (8) (a) Krishnan, M. S.; Brakaspathy, R.; Arunan, E. Chemical Education in India: Addressing Current Challenges and Optimizing Opportunities. J. Chem. Educ. 2016, 93, 1731−1736. (b) Pienta, N. J. Innocents Abroad: A Journal’s Outreach to India. J. Chem. Educ. 2013, 90, 1−2. (c) Pienta, N. J. Innocents Abroad, Part II: A Glimpse at Chemical Education in India. J. Chem. Educ. 2015, 92, 399−400. (9) Cardinal, P.; Greer, B.; Luong, H.; Tyagunova, Y. A Multistep Synthesis Incorporating a Green Bromination of an Aromatic Ring. J. Chem. Educ. 2012, 89, 1061−1063. (10) (a) Eby, E.; Deal, T. S. A Green, Guided-Inquiry Based Electrophilic Aromatic Substitution for the Organic Chemistry Laboratory. J. Chem. Educ. 2008, 85, 1426−1428. (b) Burtch, E. A.; Jones-Wilson, T. M. A Green Starting Material for Electrophilic Aromatic Substitution for the Undergraduate Organic Laboratory. J. Chem. Educ. 2005, 82, 616−617. (11) Brahmachari, G.; Laskar, S.; Sarkar, S. A green approach to chemoselective N-acetylation of amines using catalytic amount of zinc acetate in acetic acid under microwave irradiation. Indian J. Chem. 2010, 49B, 1274−1281. (12) Roy, S. C.; Guin, C.; Rana, K. K.; Maiti, G. An efficient chemo and regioselective oxidative nuclear bromination of activated aromatic compounds using lithium bromide and ceric ammonium nitrate. Tetrahedron Lett. 2001, 42, 6941−6942. (13) Ali, A. M.; Siddiki, S. M. A. H.; Kon, K.; Shimizu, K. I. Fe 3+ exchanged clay catalyzed transamidation of amides with amines under solvent-free condition. Tetrahedron Lett. 2014, 55, 1316−1319.

to all undergraduate laboratories. The goal of this experiment is to combine green chemistry and fundamental organic chemistry into one common platform that blends learning process and laboratory techniques.

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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.6b00749. Principles of green chemistry, precautionary measures, spectroscopic data (IR, 1H NMR, and 13C NMR), experimental procedures, pictorial presentation of Nacetylation and bromination, and discussion of students’ evaluation data (PDF, DOC)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Anuradha Mukherjee: 0000-0003-3185-8563 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The undergraduate students who successfully completed this experiment in the UC-206 lab course at the undergraduate chemistry lab, IISc, are gratefully acknowledged. We are grateful to Hanudatta S. Atreya for providing the NMR facility at NMR Research Centre, IISc. We are also thankful to UG chemistry coordinator, UG dean, and associate deans for providing facilities at the undergraduate laboratory. We thank the teaching assistants of this course (UC-206).

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REFERENCES

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DOI: 10.1021/acs.jchemed.6b00749 J. Chem. Educ. XXXX, XXX, XXX−XXX