Chem 241 Lab Manual - Lab 4 - Selectivity of Aromatic Bromination

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CHEMISTRY 241 Organic Chemistry Laboratory 1 Lab Manual Lab 4 Selectivity of Aromatic Bromination Professor Lawrence Goldman Professor Tomi Sasaki Department of Chemistry University of Washington
Chemistry 241 Lab 4: Selectivity of Aromatic Bromination 2023-2024 2 L AB 4: S ELECTIVITY OF A ROMATIC B ROMINATION Scenario: Seeing that the two ketones in diacetylferrocene could either be added on the same ring or opposite rings has made you curious about how someone could predict the selectivity of aromatic bromination. When a monosubstituted benzene reacts one time, which isomer will form? You decide to test this on a series of benzene derivatives. Your first task will be to determine what benzene derivatives to use. Benzene is known to cause leukemia, and it doesn’t matter where the bromination occurs so that’s out. You heard from a colleague that when she tried to brominate nitrobenzene and benzaldehyde, the reaction took several days. You don’t want to wait that long, so you decide to limit yourself to more reactive benzene derivatives. You think back to Chem 238 and different activated and deactivated benzene derivatives. Based on what you learn in class, you decide to study N,N-dimethylaniline, acetanilide, and phenol. Then you look up how harmful and corrosive phenol is, so you decide to replace it with anisole. Now that you have your candidate molecules, your task is to react them with bromine to see what product forms ortho, meta, or para. But there’s another catch, liquid bromine is itself fairly hazardous. So instead of using bromine directly, you’ll instead use N -bromosuccinimide, a reagent that is safer and generates Br 2 over time. Hopefully the isomer(s) you make will match up with what you learned in lecture, you’d hate to think that your instructor lied to you. Once you get a product, you’ll also need to use the right purification method to make sure you only have 1 brominated product. And you’ll need the right analytical tool to make sure you can tell the difference between the ortho, meta, and para isomers. Theory: The classic method of brominating an aromatic compound is to use Br 2 with a Lewis acid catalyst, such as FeBr 3 . The first step is the reaction between bromine and the Lewis acid: The positively-charged bromine ion then reacts with the aromatic ring in an electrophilic aromatic substitution reaction: When substituted benzenes undergo electrophilic aromatic substitution reactions, both the reactivity and the orientation of the electrophilic attack are affected by the nature of the substituent(s) on the benzene ring. Generally the meta position is relatively unaffected by the substituent, while the ortho and para positions may either be stabilized or destabilized. A catalyst (such as a Lewis acid) may or may not be necessary depending on how reactive the substrate is.
Chemistry 241 Lab 4: Selectivity of Aromatic Bromination 2023-2024 3 Purpose: The purpose of this experiment is to determine the relative selectivity of several substituent groups - the acetamido group ( NHCOCH 3 ), the amino group ( NH 2 ), and the methoxy group ( OCH 3 ). You will experiment, you will study the relative reactivities of acetanilide, N,N-dimethylaniline , and anisole in an electrophilic aromatic bromination reaction. Each student will carry out the bromination of one of the compounds shown above. Melting points and NMR spectroscopy will be used to identify products. By sharing your data, you will have information on the products of reactions of each of the starting materials. You will also compare the selectivity you observe with what you learn in lecture. Note that some of the products are liquids, For these compounds you will still be able Pre-lab Information: There is 1 pre-lab quiz for this experiment. Reading: PLKE Experiment 44 and Loudon 6th 16.4-16.5 or McMurry 5.1, 5.4, 5.7, and 5.8. Melting points of possible brominated products: Reactant Ortho mp (C) Meta mp (C) Para mp (C) N,N-dimethylaniline < 0 (liquid) 11 (liquid) 53 Anisole 3 (liquid) 2 (liquid) 13 (liquid) Acetanilide 99 87 168
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Chemistry 241 Lab 4: Selectivity of Aromatic Bromination 2023-2024 4 Safety Information: In this experiment, you will be using dilute hydrochloric acid, which is toxic and an irritant to the eye, skin, and digestive and respiratory tracts. NOTE Using alternative reagents. Liquid bromine has several safety hazards that make it undesirable to use in the lab. Instead, you will be using N -bromosuccinimide (NBS). This reagent has fewer health hazards than liquid bromine, though it is still an irritant to the eyes, skin, and respiratory tract. Notebook Notes: While you should include safety and chemical/physical properties for ALL 3 reactants, you only need to include yield calculations and safety information for 1 of the 9 potential products. You can assume that all possible brominated products have the same safety hazards. Additionally, make sure to note any and all color changes that occur during the reaction. P ROCEDURE : The procedure for the reaction is the same for all starting materials. However, the work-up (extraction and purification) is different, depending on which substrate on which the reaction was performed. Reaction: Into a 1 dram vial, add 0.95-1.05 mmol of anisole, acetanilide, or N,N-dimethylaniline. (For liquids, assume that 1 drop is equal to 0.015 g.) Then, add 2 mL of reagent-grade acetone and0.95-1.05 mmol of NBS. Make sure that you use at least as many mmol of NBS as aromatic reactant. Add one drop of 1 M HCl. The solution should turn a deeper/brighter yellow upon this last addition. At room temperature, lightly agitate the solution by shaking it until it becomes colorless. If there is no color change after 5 minutes, continue on to the next step anyway. Transfer the solution to a small beaker, using as little excess reagent-grade acetone as necessary to completely transfer it, and evaporate the solvent using the air line. Once the solid is dry, add 5 mL of hexanes, then put the beaker in an ice bath for 5 minutes to precipitate as much solid as possible. From here, follow the procedure corresponding to your starting material. Anisole and N,N-dimethylaniline Work-Up: Pre-weigh a beaker that you will use to collect your final product. The solid that was precipitated is reacted succinimide (NBS without its bromine). Decant the hexanes off and put it in a separate container. Remember: The hexanes now contains your product. Do not throw it away! Place the beaker with the hexanes solution into a hot water bath to evaporate off the solvent. What is left should be your product. Note that for anisole, it will be a liquid. For N,N- dimethylaniline it may be a solid or liquid. If it is a waxy solid, you might not be able to get a melting point. If your product is a solid, take a melting point. Acetanilide Work-Up: The brominated product will precipitates along with succinimide, so you will need to separate them. Succinimide is soluble in water while your brominated product is not. Decant off the hexanes. Add 5 mL of room temperature DI water to the solid to dissolve succinimde. Filter the mixture via vacuum filtration with water aspiration and collect the solid. Wash the crystals on the filter with a few milliliters of DI water, then allow it to dry on the filter. This solid should be your product. Take a melting point. Solid products with melting points less than 60C may be isolated as liquids/oils if they have significant amounts of impurities.
Chemistry 241 Lab 4: Selectivity of Aromatic Bromination 2023-2024 5 Waste Disposal: All excess liquid starting materials and hexanes, as well as any liquid products after characterization , can go into the Organic Waste jug. Excess DI water or HCl and the aqueous washes and filtrate can go into the Aqueous Waste jug. Excess solid starting materials (acetanilide and NBS), as well as solid products after characterization , can go into the Solid Waste jug. NMR Spectroscopy and Analysis: This is the first experiment where you will obtain your own NMR spectra, and multiple NMR solvents will be in use. The correct NMR solvent MUST be selected before you acquire NMR data. If you choose the wrong solvent in the software, the chemical shift scale will likely be skewed; some peaks may be missing entirely. This can NOT be fixed using MNova, and you will be left with unusable data. You will form groups of 4 students who all used the same reactant. 1 student from each group will prepare an NMR tube of their product by dissolving 30-40 mg of their product (in a small beaker/vial/test tube) in 0.6 mL of NMR solvent. Use DMSO-d6 if you started with acetanilide, and CDCl 3 if you started with anisole or N,N-dimethylaniline. You can acquire an NMR spectrum either at the end of lab 4, or during the reaction on lab 5 ALL students in the group should save their products in case it’s necessary for multiple students to combine their products to reach 30 mg. Each student will process and analyze this NMR spectrum and answer questions about it for the lab report. Using the melting point and NMR spectrum, determine which brominated product you have. On the Google sheet, every member of the NMR group must enter their individual melting point data and 1 member of the NMR group must enter their NMR result. This must be done by 6pm On the assigned day (see calendar in the syllabus) Any students who have not entered their data onto Canvas by the deadline risk losing points. Appendices: For this experiment, you will need information contained in Appendix I: NMR Spectrometer Instructions, Appendix II: Literature Searching, Appendix V: WebMO Computational Instructions, and Appendix VI: Useful Data Tables for Analyzing Spectra.
Chemistry 241 Lab 4: Selectivity of Aromatic Bromination 2023-2024 6 Computational Exercise Goal: How can we use WebMO to predict the selectivity of a reaction? Would we expect the major product to be ortho, meta, or para? We will use 3 types of data from WebMO to predict this. First, we will look at the partial charges on each benzene carbon to see which is the most nucleophilic. Natural population charges are more accurate than partial charges, but require a separate calculation. Second we will compare the energy of each intermediate to see which intermediate is most stable. Markovnikov’s rule says the most stable intermediates will lead to the major products. Third, we will analyze how much the methoxy group involved in resonance with the benzene ring for each intermediate. Ideally, these three techniques will make a similar prediction about which product will be the major product.. Computational instructions: Do the following for anisole , regardless of which reactant you will be using in the experiment 1) A geometry optimization (Optimize + Vib Freq) at the B3LYP/3-21G level of theory for anisole 2) A geometry optimization (Optimize + Vib Freq) at the B3LYP/3-21G level of theory for the ortho, meta, and para bromomination intermediates of anisole. Make sure the positive charge is on the correct atom and that in the submitted job, the charge is +1 and the multiplicity is “singlet” 3) For all 4 of the compounds/ions, carry out a “bond order” calculation on the optimized geometry at the same level of theory. When you are recording the charges, make sure to use the “natural population analysis” section of the “bond order” calculation output. Do NOT use the “partial charge” section of the output. You do NOT have to do a separate natural bond orbital job because that section is included in the bond order output. Estimated computational time: 1 hour Helpful hints make sure each molecule is in a separate job. Ensure that each ion has a +1 charge. The “stoichiometry” line of the WebMO output should end with (1+). If the “stoichiometry” line of the WebMO output ends with (2), then you calculated a radical, not a cation and your energies are meaningless. You can save some time by using the neutral compound as a template for drawing the intermediates. For the intermediates, it doesn’t matter which resonance form you draw since WebMO should converge on the resonance hybrid structure. Make ABSOLUTELY no changes between the geometry and bond order calculations, not even cleaning up the structure or applying symmetry.
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Chemistry 241 Lab 4: Selectivity of Aromatic Bromination 2023-2024 7 L AB 4: S ELECTIVITY OF A ROMATIC B ROMINATION Name: __________________________________________ Section:_______ GRADING each section below is worth 1 point. You must earn 4 out of 5 points to get credit for this lab report. You do not need perfect scores on each section to get credit for that section. SECTION 1 Notebook Include all of your notebook pages for this experiment. Each of the following sections will be graded 0/1: Goal Safety information Reaction table Procedure Data/observations Conclusion If 4 of the 6 notebook parts are successfully completed, you will get credit for this section. SECTION 2 Data. Answer the following questions. If you get 5 of 7 pieces, you will get credit for this section. 1) (1 piece) Data entered accurately and on time on the Google Sheet Starting compound____________________________ 2) (1 piece) weight of your pure brominated product ______ % yield _______ (show calculations) 3) (1 piece) Draw the major product that you isolated. 4) (2 pieces)) Draw the structures of the major product obtained by the class for each of the other 2 reactants
Chemistry 241 Lab 4: Selectivity of Aromatic Bromination 2023-2024 8 5) (1 piece) If your yield was below 30% or above 100% explain what went wrong and how it might be fixed. If your yield was between 30%, and 100% state that. 6) (1 piece) If your mp was more than 10C off from the expected value explain what led to the low purity and how it might be fixed. If your mp was within 10C, state that. If your product was a liquid, state that. SECTION 3 Spectroscopy. Answer the following questions. If you get 2 of 3 pieces, you will get credit for this section. 3A NMR (3 pieces). Attach your NMR spectrum. Make sure all chemical shifts and integrations are labelled for all peaks, including TMS and solvents. The integration values should match the structure. Draw the compound corresponding to the major product, and label the Hs on the structure that corresponds to each peak SECTION 4 Analysis questions. Answer the following questions. If you get 5 of 7 pieces, you will get credit for this section. 1) Consider the intermediate formed from your reactant on the way to make your major product. Draw the most dominant resonance structure for it. 2) In Chem 238, you learn that compounds are either ortho/para directors or meta directors. Did you obtain both the ortho and para products? If not, briefly explain why only 1 of the ortho and para products was formed.
Chemistry 241 Lab 4: Selectivity of Aromatic Bromination 2023-2024 9 3) Why was the meta product not a major product for your reactant? 4) Give 1 advantage to using melting point to ID your product and 1 advantage to using NMR. 5) (2 pieces) According to WebMO, is anisole an ortho/para director or a meta director. How does this compare to your experimental results? You must explicitly reference at least 2 types of WebMO data (partial charges, bond orders, or energies) 6) Give 1 advantage to determining the ortho/meta/para directing effect of aromatic compounds experimentally, and 1 advantage to using WebMO. SECTION 5 Safety You don’t have to submit anything. You will get credit as long as you were prepared for lab and didn’t violate any lab safety policies
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