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Student Notes: Greener Brominations of Stilbene

(Reference: Mckenzie, L.C., Huffman, L.M., and Hutchison, J.E., Journal of Chemical Education, 2005, 82, 306-310)

ATTENTION STUDENTS:

This lab will be completed over a 3 week period. During the first 2 labs you will be completing reactions (Parts A, B, and C). By the third week you all should be characterizing. Do not do any characterization until all products have been made. Some characterization involves crude product, be sure to keep a small portion when needed. Do not dispose of any products at any time, please keep everything in a properly labeled vial. Both IR and melting points will be used to aid in characterization. Also, Part D can be completed on your own time. I suggest after each reaction is completed that you start to gather the information that will be needed for calculations (see the table at the end of this document). Begin to organize your data as you go along (HINT: This will not be a lab report that you can complete at the last minute). Since this lab will be over a 3 week period, this will serve as three labs, and the entire lab will be worth 150 points. The points will be divided up as usual, but just take those amounts and multiply by 3. This means that your lab report will be worth 60 points. You will also find that there are no pre-lab questions or questions throughout the experiment. There will be no questions section to include in your report. You will be given automatically 15 points for this section. Please take the time to come prepared for these experiments. This is an involved synthesis; careful preparation and time are needed to do well.

In this experiment you will:

Apply different techniques and chemicals to successfully brominate stilbene Learn to synthesize and save materials using greener methods Characterize your products using various types of spectroscopy Use green chemistry metrics to asses the efficacy of bromination reactions

Pre-lab Assignment

Readings: Read the introduction and procedures of this experiment carefully, look up any additional information that is unclear or requires more of an explanation.

Safety

Safety glasses and gloves must be worn at all times Handle all reagents and solvents with care Dispose of all waste in their appropriate containers

Introduction

In order to obtain complex molecules, it is often necessary to introduce more reactive functionality than is possible from simple hydrocarbons. Alkenes (olefins) ­ hydrocarbons containing the carbon-carbon double bond functional group ­ may be "halogenated" to form alkyl halides, which are then capable of undergoing a variety of further chemical transformations. In the experiments described in Parts A and B, you will brominate an alkene, trans-stilbene, as shown in Figure 1. This reaction is representative of any other alkene bromination.

Figure 1: The bromination of trans-stilbene Bromination of an alkene is an example of an addition reaction in which bromine adds across the double bond to yield a vicinal dibromide. A commonly accepted pathway for this addition involves an ionic mechanism in which the electron-rich alkene acts as a nucleophile (a species that attacks centers bearing more positive charge) and the bromine is the electrophile (a species that that is attracted to and tends to accept electrons). As bromine and the alkene approach one another, the Br­Br bond becomes polarized (becoming more positive near the alkene and more negative at the other end). The more positively charged Br atom is transferred to the alkene to yield a bromonium ion and a bromide anion. In a second step, bromide attacks one of the carbon atoms of the cyclic bromonium ion to open the three-membered ring and yield the vicinal dibromide. The second step is a bimolecular nucleophilic substitution reaction (SN2). The net result of this reaction is anti addition of bromine, as opposed to syn addition.

Figure 2: General mechanism of bromination across a double bond. The Br-Br bond becomes polarized, so the bromine attacks first as an electrophile and then as a nucleophile. Traditionally, this reaction is performed in a solvent, like methylene chloride or carbon tetrachloride (both suspected carcinogens), that will not participate in the reaction but will dissolve the alkene. Some brominations may also be carried out in glacial acetic acid, a volatile and corrosive liquid. The traditional reagent, elemental bromine, is also dangerous to handle, because it is highly corrosive and causes severe burns upon contact with the skin. While this reaction works very well on most substrates, it can be dangerous to do in an instructional laboratory setting. For these reasons, two greener alternatives to this reaction are presented.

Part A: Bromination of trans-stilbene with pyridinium tribromide An alternative to traditional bromination is presented below. The largest modification is that instead of using liquid bromine, an alternative reagent, pyridinium tribromide, popularized by Djerassi and Scholz (1), is used. This reagent provides for gradual release of bromine into the reaction medium because it is in rapid equilibrium with pyridinium hydrobromide and molecular bromine (see Figure 3). An additional advantage of pyridinium tribromide is that it is an easily weighed solid, in contrast to liquid bromine. As the bromine is consumed in the reaction, more is produced by the pyridinium tribromide. Because the dangerous reagent is produced in situ, it no longer needs to be handled directly (2). Another benefit of this reaction is that a more benign solvent, ethanol, can be used instead of a chlorinated solvent.

Figure 3: Equilibrium between pyridinium tribromide and pyridinium hydrobromide and bromine The biggest drawback to this reaction is the lower atom economy as compared to the traditional bromination procedure. Aside from the desired product, pyridinium hydrobromide is also produced as waste. Pyridinium tribromide also is corrosive and can cause significant damage to metal equipment, especially balances.

Experimental Procedure SAFETY PRECAUTIONS: Pyridinium tribromide is corrosive and is also a lachrymator. Avoid contact with this material and wipe up any spills immediately, particularly on the balance. Ethanol is flammable; do not use open flames near flammable solvents. Reaction 1. Into a 125-ml Erlenmeyer flask, place 40 ml of ethanol and 2.0 g of (E)-stilbene along with a magnetic stir bar. (Be sure to record the exact mass of the stilbene you use.) Clamp the Erlenmeyer flask in place on a hot plate (3). Using the hot plate for both heating and stirring, dissolve the stilbene (4). Wearing disposable gloves, add 4.0 g of pyridinium tribromide and mix thoroughly. You may need to wash down the inside of the flask with a little ethanol to make sure that all the solid material dissolves in the reaction medium. After another 5 min of heating, remove from heat, being careful not to burn yourself on the glassware. The product dibromide will immediately begin to precipitate or crystallize.

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Workup and Isolation 4. Let the reaction mixture cool to room temperature and then chill the mixture in an ice bath. Collect the product by vacuum filtration. Set aside a small amount of this "crude" product so that you can measure its melting point later. Wash the crystals with a small amount of ice-cold methanol to remove any adsorbed pyridinium salts. Dry your compound (by drawing air through it while it sits in the filter funnel).

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Characterization 6. Measure the melting point. Also measure the melting point of your crude material Determine the percentage yield of this purified product (you will need its mass). Retain a sample of your purified stilbene dibromide in a vial for later analysis using Infrared Spectroscopy (IR).

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Part B: Bromination of trans-stilbene with hydrogen peroxide and hydrobromic acid The bromination with pyridinium tribromide is an example of a reaction which has been made safer, yet has considerable opportunities for improvement. Although the solvent and bromination reagent are less hazardous, pyridinium tribromide is corrosive and can cause significant damage to metal equipment. While molecular bromine has been removed from the teaching lab, the hazard is not eliminated entirely because the reagent is synthesized from pyridine and bromine. Another drawback to this reaction is the relatively poor atom economy; while the desired product is obtained, a quantitative amount of pyridinium bromide is produced as waste. Recent literature suggests greener methods of bromination which have high atom economy, use less corrosive materials, and eliminate liquid bromine and chlorinated solvents (5,6). In this reaction (see Figure 4), hydrobromic acid and hydrogen peroxide are used to generate molecular bromine, and the solvent is ethanol. The by-product in this reaction is just water.

Figure 4: Molecular bromine is produced in situ by the oxidation of hydrobromic acid by hydrogen peroxide Experimental Procedure SAFETY PRECAUTIONS: Care must be taken when using concentrated acid and/or 30% hydrogen peroxide. Both are corrosive, can cause eye and skin burns, and are harmful if inhaled. Be careful to avoid contact with skin and refrain from breathing these compounds. Neutralize all excess acid in the provided containers, and clean up all spills immediately. Acid will make holes in your clothes (and your skin), so try not to spill any. Ethanol is flammable so use caution.

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Prepare a 100 ml round-bottom flask with a stir bar, and prepare a 90-100 ºC water bath. Measure out 0.5 g stilbene, and add it to the flask with 15 mL of ethanol. Fit with a reflux condenser and heat the reaction with stirring. Allow the solids to dissolve. Add a little more ethanol if everything doesn't go in. Once dissolved, slowly add 0.8 mL of HBr (about 2.5 equivalents), and let the solution heat and stir. The precipitate caused by the addition of acid should go back into solution, but it may not. Continue even if it does not all go back in. Measure out 0.8 mL of 30% hydrogen peroxide (also about 2.5 equivalents) and add it dropwise to the reaction. The color should change from clear and colorless (or cloudy white if the precipitate did not go back in) to dark golden yellow. Let the reaction reflux and stir for about 20 minutes or until the color disappears and the mixture becomes a cloudy white. Remove the reaction from the heat and let it cool. Once at room temperature, neutralize (pH 5 to 7) the solution with a concentrated NaHCO3 solution. It may only take a little, depending on how much excess acid you have. Check pH with pH paper. Once neutralized, put the flask on ice to further cool it and cause more crystals to precipitate. Collect the crystals by vacuum filtration, rinsing with very cold water and a little bit of very cold ethanol. Let air flow over the product to help dry it. Record your yield and product melting point (literature m.p. 241°C dec.). If time permits and you find it necessary, recrystallize the stilbene dibromide from ethyl acetate. Retain a sample for IR spectroscopy.

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Part C: Debromination of stilbene dibromide Vicinal dibromides, such as stilbene dibromide, can be readily debrominated by zinc in either acetic acid or ethanol to produce the corresponding alkene. Literature suggests two possible mechanisms for this reaction, a concerted two electron reduction by the zinc or two single electron transfers in rapid succession (7). Each of these mechanistic paths would lead to the single stereoisomer which is formed by this reaction (see Figure 5).

Figure 5: Debromination of stilbene dibromide by zinc metal either through a concerted two electron reduction or two rapid single-electron transfers

In this procedure, you will be debrominating the product from the above bromination reactions in order to recycle it for future laboratory experiments. The solvent, reagent, and byproduct are all non-toxic, and the procedure is neither time- nor energy-intensive. Although a bromination followed immediately by removal of the added bromine atoms would not usually be viewed as using green chemistry, the recycling and reuse of trans-stilbene improves the efficiency of the reaction and reduces the waste, thereby improving the greenness of the reactions. Experimental Procedure SAFETY PRECAUTIONS: Zinc and ethanol are flammable; do not use open flames near these compounds. Although no specific health risks are associated with zinc dust, always avoid inhalation of particulate matter. The by-product, zinc dibromide, is corrosive and can cause burns. 1. 2. 3. 4. Prepare a 100 ml flask with a stir bar, and prepare a hot (90-100 ºC) water bath. Measure out 0.5 g stilbene dibromide, and add it to the flask with 10 mL of ethanol. Add 1.25 equivalents of zinc powder. Fit with a reflux condenser and heat the reaction to reflux with stirring. Allow the reaction to reflux and stir for 30 minutes. Prepare a hot filtration set-up with a stemless funnel, 50 mL Erlenmeyer flask, fluted filter paper, and a watch glass. Just before the reaction is complete, add 3 mL of ethanol to the Erlenmeyer flask and heat the set-up. Hint: Many technique-based texts do not emphasize the importance of preheating a hot filtration system to reflux, however it is important that the filter paper is kept hot throughout the filtration. Remove the reflux condenser from the reaction. Using the clamp as a handle, pour a small amount of the hot solution slowly from the round-bottom flask into the filter paper. Replace the watch glass and allow the hot solution to filter. Repeat until all solution is filtered. Remove the flask from the heat and allow it to cool to room temperature. A few crystals should begin to form. Place the flask in ice and allow crystallization to proceed. Collect the crystals by vacuum filtration, rinsing with a little bit of very cold ethanol. Let air flow over the product to help dry it. Record your yield and product melting point (literature m.p. 122-124 ºC).

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Part D: Assessing the efficiency of bromination reactions: An introduction to green chemistry metrics This section introduces the evaluation processes used for green chemistry and describes some of the metrics employed in the process. As an additional exercise, you also can compare your results to the traditional bromination procedure involving liquid bromine in a halocarbon solvent, such as that featured in reference 8. 1. In order to assess the greenness of a chemical reaction, each alternative procedure must be evaluated to identify hazardous materials or inefficient procedures. Read over both bromination procedures in this handout. Which reaction do you think is the greenest? Why? Write a balanced equation for each reaction. Metrics allow for measured, objective analysis for comparison of competing procedures, emphasizing measures of efficiency and cost, in addition to the comparison of chemical hazards. Atom economy (9) was developed to quantify the theoretical reaction efficiency and calculates the fraction of reactants converted to the product. Clear explanations of atom economy and its applications are provided by Trost in articles in Science and Accounts of Chemical Research (9,10).

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Calculate the atom economy for both the reaction that you performed and the alternative bromination procedure. How do they compare? Reaction from Part A, pyridinium tribromide:

Reaction from Part B, hydrogen peroxide and hydrobromic acid:

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Effective mass yield uses the actual masses of reagents used and products generated in the reaction to gauge reaction efficiency and takes into account relative toxicity of the method by focusing only on the hazardous components of the waste stream. Hudlicky et al. present a thorough description of effective mass yield in their article in Green Chemistry (11). Calculate the effective mass yield for both the reaction that you performed and the alternative bromination procedure. For this purpose, consider ethanol as a benign material. How do they compare?

Reaction from Part A, pyridinium tribromide:

Reaction from Part B, hydrogen peroxide and hydrobromic acid:

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Use the following procedure to perform an economic analysis of the preparation of dibromostilbene via each route: a. Identify the costs of all required materials. Use the largest quantity listed in the catalog of either Aldrich Chemical Company or Acros Organics. Be sure to include all substances used, whether as reagents, catalysts, or solvents. Record the total amounts of each material used and the waste generated. Calculate the cost for each starting material, reagent, and solvent and determine the total cost of the experiment. Add in costs for waste generated. Assume it will cost $25/L to dispose of liquid waste and $25/kg to dispose of solid waste and that products and solvents are not recycled. After consideration of the above calculations, which reaction do you think is the greenest? Why? Is this different from your original assessment? Which metric affected your decision the most? What are some of the challenges that you noticed in applying metrics to evaluate the greenness of reactions?

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Notes 1. 2. Djerassi, C.; Scholz, C. R. J. Am. Chem. Soc. 1948, 70, 417-418. When a reagent is generated in (rather than added to) the reaction medium it is said that the reagent is prepared in situ. The purpose of the clamp is to allow you to remove the flask from the hot plate without burning yourself in the event that the solution starts to boil vigorously. Be careful not to turn the hot plate up too far ­ the hot plate will be slow to heat at first, and then heat extremely fast. Once hot, it will take a very long time to cool down again! Ho, T. L.; Gupta, B. G. B.; Olah, G. A. Synthesis 1977, 676-677. Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron 1999, 55, 11127-11142. Totten, L. A.; Jans, U.; Roberts, A. L. Environ. Sci. Technol. 2001, 35, 2268-2274. Durst, H. D.; Gokel, G. W. Experimental Organic Chemistry; McGraw-Hill: San Francisco, 1987; pp 240-241. Trost, B. M. Science 1991, 254, 1471-1477. Trost, B. M. Acc. Chem. Res. 2002; 35(9), 695-705. Hudlicky, T.; Frey, D. A.; Koroniak, L.; Claeboe, C. D.; Brammer, L. E. Green Chemistry 1999, 1, 57-59.

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