Laboratory Experiment pubs.acs.org/jchemeduc
A Multistep Synthesis Incorporating a Green Bromination of an Aromatic Ring Pascal Cardinal, Brandon Greer, Horace Luong,* and Yevgeniya Tyagunova Department of Chemistry, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada S Supporting Information *
ABSTRACT: Electrophilic aromatic substitution is a fundamental topic taught in the undergraduate organic chemistry curriculum. A multistep synthesis that includes a safer and greener method for the bromination of an aromatic ring than traditional bromination methods is described. This experiment is multifaceted and can be used to teach students about protecting groups, multistep synthesis, redox reactions/titrations, electrophilic aromatic substitution, and nucleophilic acyl substitution.
KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives, Electrophilic Substitution, Green Chemistry, IR Spectroscopy, NMR Spectroscopy, Synthesis, Titration/Volumetric Analysis
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product yields are appreciably affected by the temperature and concentration dependences of the bromine-generating reagent. A multistep synthesis of 4-bromoacetanilide from aniline is presented (Scheme 1). In contrast to the old method of
lectrophilic aromatic substitution (EAS) is a fundamental concept in organic chemistry and is commonly used as the topic of an experimental exercise at the undergraduate level. These laboratory experiments enable the students to understand the directive effects of substituted functional groups on an aromatic ring.1 Quite often, traditional EAS reactions involve dangerous chemicals and require disposal methods that are expensive to the institution and hazardous to the environment. In recent years, environmental concerns have directed chemists to explore environmentally friendly methods in the preparation of various compounds.2−5 Ideally, this entails the development of procedures where reagents and products are low in toxicity and volatility, thereby diminishing environmental and health concerns during handling, use, storage, and disposal. Traditional undergraduate EAS reactions have required the use of (or created as byproducts) harmful halocarbons: one example being the synthesis of bromobenzene, a simple halogenated aromatic ring. Typical procedures to generate bromobenzene include electrophilic substitution of bromine (from Br2) onto benzene via some metal Lewis acid catalyst such as AlCl3, SbCl3, and SbCl4.6 The handling of liquid bromine is a safety concern using these methods. The organic synthesis chemical education community has developed green methods that allow students to gain experience in aromatic halogenation reactions without being exposed to the hazards presented by traditional procedures. One reagent that has shown promise in achieving this task is pyridinium tribromide, which generates elemental bromine in situ as the reaction progresses, avoiding the handling of liquid bromine.7,8 However, a large quantity of waste is produced and © 2012 American Chemical Society and Division of Chemical Education, Inc.
Scheme 1. Synthesis of 4-Bromoacetanilide
brominating using bromine in acetic acid, the bromine used to perform the bromination is generated in situ from an acidic solution of sodium hypochlorite and sodium bromide. Both reagents used to generate the bromine (sodium bromide and sodium hypochlorite, which is found in bleach) are more benign to handle than liquid bromine. The amine group of aniline should be protected prior to bromination.9 This must be done to minimize multisubstituted products. In using this greener method, the amine group is protected for two reasons. First, the protection helps minimize the production of multisubstituted products. Second, even though it was reported by Edgar and Falling10 that it is possible to selectively monoiodinate phenol without the use of a protecting group using conditions similar to what is proposed in this experiment, the amine group on aniline is a safety concern when mixed with Published: May 4, 2012 1061
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Laboratory Experiment
(29−73% from nine student trials; yields reported using acetanilide as the limiting reagent).
sodium hypochlorite because dangerous chloramines can form. Therefore, acetylating the amine group will also minimize safety concerns. The inspiration for the bromination reaction derived from previous reports of iodination reactions using NaI and NaClO, where high yields and selectivity were obtained.10,11 By using the fundamentals of the iodination reactions, the reaction was adopted for brominating conditions and the synthetic pathway was controlled to avoid the aforementioned byproducts. The new green method provides an efficient and safe way to prepare a monosubstituted product and can easily be incorporated as a preliminary reaction to further organic syntheses (e.g., amide hydrolysis, metal-catalyzed coupling). The mechanism and kinetics of generating the brominating species using the conditions reported here is complicated but can be found in the literature.12 Students who performed the bromination were required to deduce which isomer was synthesized in the bromination reaction and support their conclusion using data collected (e.g., melting point and NMR spectroscopy).
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HAZARDS Acetic anhydride and acetic acid are corrosive and can cause burns. Aniline is harmful if inhaled. Acetone, acetic acid, ethanol, and acetic anhydride are flammable. Sodium hypochlorite is an oxidizing agent and can release toxic fumes and should be used in a fume hood. Appropriate eye protection, gloves, and a lab coat should be worn in order to avoid chemical burns and contact with eyes and skin.
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CHEMICALS AND EQUIPMENT All chemicals used were standard grade obtained from commercial suppliers and used without further purification. Bleach, used as a source of NaClO, was purchased from a local grocery store. Melting points were measured using an Electrothermal melting point apparatus. Infrared spectral data were collected using a Bruker Alpha FT-IR spectrometer. 1H and 13C NMR spectra were collected on a Bruker Advance 300 spectrometer (Bo = 9.4 T) with a Bruker 5 mm solutions probe, using CDCl3 or acetone-d6 as a solvent.
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RESULTS AND DISCUSSION
The experiment was incorporated into a second-year organic chemistry laboratory program and can be completed over two 3-h laboratory periods. However, the experiment can be shortened to one period by removing the bleach titration step and consequently using a slight excess of sodium hypochlorite (the solution will be tinted a faint brown−yellow when a slight excess is available). The technical skills emphasized in this experiment included recrystallization, vacuum filtration, redox titration, recording and analyzing IR spectra, melting point measurements, preparing solutions, percent yield calculations, and NMR spectral analysis. Numerous attempts were made to determine appropriate thin-layer chromatography (TLC) conditions to separate acetanilide and 4-bromoacetanilide; however, all attempts failed. Two recent literature references mentioned that they were able to separate the two by TLC.13 The authors provided their TLC conditions for us to try, but the separation proved to be unsuccessful. It should be mentioned that using the procedure in this paper, the student’s yield of 4-bromoacetanilide may not be as high as previous syntheses (84%) that had used more hazardous conditions.9 Overall yields for the greener experiment are about 66% for an experienced chemist and 34% for undergraduate students. The difference in overall yields between the student’s and the experienced chemist’s experiment may be due to a poor decision made on solvent volume for the recrystallization of the final product. Students have a tendency of using excess solvent, and therefore minimizing the 4-bromoacetanilide recovery. One task in this experiment was to determine the volume of bleach to use since the actual concentration of sodium hypochlorite differed from the reported concentration. This step in the procedure reviewed a laboratory technique (titration) taught in the general chemistry curriculum. The titration was an interesting aspect to the overall experiment because it emphasized the relevance of a laboratory technique taught elsewhere and brought an analytical technique into the organic chemistry laboratory. The students deduced the substitution pattern and purity of the bromoacetanilide using melting point data and the supplied 1 H and 13C NMR spectra (available in the Supporting Information). In typical student data, the melting point results supported one isomer. Students recorded an IR spectrum, which reveals functional group identity, but nothing about purity or isomer identity can be confidently stated. The undergraduate student would usually expect to observe two doublets in the 1H NMR spectrum aromatic region for parasubstitution. Students normally expect the 1H NMR spectrum to be a quintessential tool for solving structure; however, in this
EXPERIMENTAL PROCEDURE
Protecting Aniline
Aniline was reacted with acetic anhydride to yield acetanilide. The reaction was quenched with a basic aqueous solution. The product was made in 75% yield by an experienced chemist and 72% by students (34−91% from nine student trials). Hypochlorite Concentration Determination in Bleach
The sodium hypochlorite concentration in bleach was determined by a redox titration using sodium thiosulfate and sodium iodide. The sodium hypochlorite concentration advertised on the bleach bottle was 6% (about 0.8 M). The actual concentration determined by titration was found to be less than 3%. This discrepancy could be a function of how (and how long) the bleach bottles have been stored. Brominating Acetanilide
Acetanilide and sodium bromide were mixed in a solution of acetic acid and ethanol and then cooled in an ice bath. The appropriate amount of bleach was added to the cooled solution such that there was about 5% mole excess of sodium hypochlorite. Following a maximum reaction period of 25 min, the reaction was quenched with sodium thiosulfate and sodium hydroxide. The addition of sodium thiosulfate and sodium hydroxide precipitated the product. 4-Bromoacetanilide is soluble in acetic acid, and by neutralizing the acetic acid with sodium hydroxide, product recovery increased. The crude product was recrystallized using 50% ethanol in relatively high purity (experimental melting point of the product was found to be 166−167 °C). The 4-bromoacetanilide was made in 88% yield by an experienced chemist and 50% yield by students 1062
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situation, the 1H NMR spectrum is unreliable because of second-order spin−spin coupling in the aromatic region (when CDCl3 is used as the solvent). When using acetone-d6 as a solvent, it is possible to resolve the doublets; however, the acetyl CH3 resonance is hidden under the residual acetone solvent signal in the 1H NMR spectrum. The bromoacetanilide product is also soluble in acetone-d6 (unlike CDCl3), which helps with the 13C NMR data acquisition. Therefore, to the students’ surprise, the 13C NMR spectrum becomes important in identifying the isomer. Substitution in ortho, meta, and para positions are expected to give rise to six, six, and four resonances in the aromatic region in the 13C NMR spectrum, respectively. In the provided 13 C NMR spectrum of bromoacetanilide, it is obvious that there are four aromatic carbons. The exercise of examining the 13C NMR spectrum allows students to see how chemical and magnetic equivalency in NMR spectroscopy can be used to distinguish structural isomers of organic compounds. Many of the experiments at the second-year level are onestep reactions. Because this reaction is composed of two steps from aniline, it provides an opportunity to teach the students how to calculate overall yields of a multistep synthesis (i.e., as the product from the yield of each step). The student assessment for this experiment was divided into three parts: sample quality, laboratory report, and peer evaluation. The quality of the sample was based on visual inspection of the 4-bromoacetanilide sample; samples that were white and crystalline and free of visible contaminants were awarded full value. Students were organized into groups and asked to produce a laboratory report containing all components of a full report (questions and format available in the Supporting Information). Peer evaluation, conducted according to the percentage method,14 was deemed necessary for ensuring everyone contributed to the project.
Laboratory Experiment
ACKNOWLEDGMENTS We would like to thank the CHEM 2220 students (winter 2010 and summer 2011 term) at the University of Manitoba for their input concerning the experiment. As well, we would like to thank Kirk Marat for use of the University of Manitoba NMR facilities.
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REFERENCES
(1) Beishline, R. R. J. Chem. Educ. 1972, 49, 128−129. (2) Yadav, J. S.; Subba Reddy, B. V.; Swamy, T.; Shankar, K. S. Monatsh. Chem. 2008, 139, 1317−1320. (3) Pérez-Mayoral, E.; Martín-Aranda, R. M.; López-Peinado, A. J.; Ballesteros, P.; Zukal, A.; Č ejka, J. Top. Catal. 2009, 52, 148−152. (4) Wolfson, A.; Saidkarimov, D.; Dlugy, C.; Tavor, D. Green Chem. Lett. Rev. 2009, 2, 107−110. (5) Beheshtiha, Y. S.; Heravi, M. M.; Saeedi, M.; Karimi, N.; Zakeri, M.; Tavakoli-Hossieni, N. Synth. Commun. 2010, 40, 1216−1223. (6) Smith, M. B. Organic Synthesis; McGraw-Hill: New York, 1994; p 186. (7) Merker, P. C.; Vona, J. A. J. Chem. Educ. 1949, 26, 613−614. (8) McKenzie, L. C.; Huffman, L. M.; Hutchison, J. E. J. Chem. Educ. 2005, 82, 306−310. (9) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook of Practical Organic Chemistry; Longman Scientific & Technical: New York, 1989; p 918. (10) Edgar, K. J.; Failling, S. N. J. Org. Chem. 1990, 55, 5287−5291. (11) Eby, E.; Deal, S. T. J. Chem. Educ. 2008, 85, 1426−1428. (12) Kumar, K.; Margerum, D. W. Inorg. Chem. 1987, 26, 2706− 2711. (13) (a) Kumar, L.; Mahajan, T.; Sharma, V.; Agarwal, D. D. Ind. Eng. Chem. Res. 2011, 50, 705−712. (b) Kavala, V.; Naik, S.; Patel, B. K. J. Org. Chem. 2005, 70, 4267−4271. (14) Team-Based Learning: Two Methods for Calculating Peer Evaluation Scores. http://www.teambasedlearning.org/Resources/ Documents/TBL%20-%202%20methods_peer%20eval%20scores.pdf (accessed Apr 2012).
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CONCLUSION This article describes an easy and safe multistep reaction for demonstrating the use of a protecting group, an electrophilic aromatic substitution reaction, and how redox reactions can be used in organic chemistry. The products are solids and, therefore, are easy for the students to manipulate for purification. A variety of laboratory techniques are exercised in this experiment: recrystallization, redox titration, IR and NMR spectroscopy, and vacuum filtration. This experiment also reinforces lecture material regarding nucleophilic acyl substitution, benzene-ring substituent directing effects, redox reactions, multistep synthesis, and protecting groups. Additionally, the procedure demonstrates to students that alternative and safe pathways can be rationalized and developed that accomplish an identical synthetic goal as traditional methods.
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ASSOCIATED CONTENT
S Supporting Information *
Instructor notes; student handouts; NMR spectra. This material is available via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest. 1063
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