Experiment 5: Synthesis and Bromination of Phenacetin | Lab Reports Chemistry

E5-1

Experiment 5 – Synthesis and Bromination of Phenacetin:

A Substitution Puzzle

Scheme 1. Overview of two-step synthesis of bromophenacetin from acetaminophen.

In this experiment, students will convert the acetaminophen (the active ingredient in

Tylenol) into phenacetin to exemplify a Williamson ether synthesis. The product will be analyzed

by melting point, chemical tests, TLC, and IR and 1H NMR spectroscopy. Phenacetin will then

be subjected to an electrophilic aromatic substitution (EArS) reaction to introduce a bromine into

the ring at a yet to be determined position. Melting point and 1H NMR and IR spectroscopy will

be used to analyze the brominated product. 1H NMR and melting points will be used to

determine the substitution pattern of the bromophenacetin.

Students will work individually to carry out each step of the experiment and collect all

data, with the exception of shared NMR spectra to be posted online. Students will be assessed

on their lab technique throughout the experiment, including following instructions, handling

chemicals and equipment, as well as product yields to a reasonable extent. Technical writing

will be emphasized throughout the experiment. Students will write the abstract and/or

experimental methods sections in the second week of lab and bring a respectable draft of each

to the third week of lab. Lab-mates will proofread each other’s work using the writing guidelines

online as well as the specific notes for this report on p. E5-6 of this document.

Notebook Preparation – start a new notebook page each week

• Purpose: Reaction scheme if performed, or structure (starting material, reagent, solvent,

all possible products)

• Reagent table: List the amounts (mg or mL and mmol), molar equivalents (“equiv.”), and

physical properties (MW, bp or mp, density, one-word hazard) of each chemical in the

reaction scheme or process.

• Hand-written procedure: self-explanatory

• Safety & Clean-up: copy the pertinent information from Table 1 at the end of each part

EXPERIMENTAL PROCEDURE

Week 1 – Synthesis of Phenacetin, Williamson Ether Synthesis

Reaction Set Up. Obtain 360 mg of acetaminophen and transfer into a dry 25-mL round-bottom

flask (RBF). Add a stir bar, 560 mg of K2CO3 (ground if necessary), 6.0 mL of acetonitrile

(CH3CN), and lastly 0.56 mL of ethyl iodide. Attach a microscale water-cooled condenser and,

after cold water is circulating, heat to reflux directly on a hot plate (medium setting) for 1 hour.

Obtain the IR of acetaminophen and work on the abstract or experimental methods during this

time. Each student must make an IR sample (nujol mull) and obtain a fresh spectrum of

acetaminophen this week (no sharing, there is ample time!).

CH3CH2I, K2CO3

CH3CN, ΔO

Phenacetin

Acetaminophen

Week 1

(reaction)

Week 2

(analysis)

KBrO3, HAc

HBr(aq)O

Bromophenacetin

Week 3

(reaction, purification, analysis)

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Experiment 5 – Synthesis and Bromination of Phenacetin: A Substitution Puzzle Scheme 1. Overview of two-step synthesis of bromophenacetin from acetaminophen. In this experiment, students will convert the acetaminophen (the active ingredient in Tylenol) into phenacetin to exemplify a Williamson ether synthesis. The product will be analyzed by melting point, chemical tests, TLC, and IR and 1 H NMR spectroscopy. Phenacetin will then be subjected to an electrophilic aromatic substitution (EArS) reaction to introduce a bromine into the ring at a yet to be determined position. Melting point and 1 H NMR and IR spectroscopy will be used to analyze the brominated product. 1 H NMR and melting points will be used to determine the substitution pattern of the bromophenacetin. Students will work individually to carry out each step of the experiment and collect all data, with the exception of shared NMR spectra to be posted online. Students will be assessed on their lab technique throughout the experiment, including following instructions, handling chemicals and equipment, as well as product yields to a reasonable extent. Technical writing will be emphasized throughout the experiment. Students will write the abstract and/or experimental methods sections in the second week of lab and bring a respectable draft of each to the third week of lab. Lab-mates will proofread each other’s work using the writing guidelines online as well as the specific notes for this report on p. E5-6 of this document. Notebook Preparation – start a new notebook page each week

Purpose: Reaction scheme if performed, or structure (starting material, reagent, solvent, all possible products)
Reagent table : List the amounts (mg or mL and mmol), molar equivalents (“equiv.”), and physical properties (MW, bp or mp, density, one-word hazard) of each chemical in the reaction scheme or process.
Hand-written procedure: self-explanatory
Safety & Clean - up : copy the pertinent information from Table 1 at the end of each part EXPERIMENTAL PROCEDURE Week 1 – Synthesis of Phenacetin, Williamson Ether Synthesis Reaction Set Up. Obtain 360 mg of acetaminophen and transfer into a dry 2 5 - mL round-bottom flask (RBF). Add a stir bar, 560 mg of K 2 CO 3 (ground if necessary), 6.0 mL of acetonitrile (CH 3 CN), and lastly 0.56 mL of ethyl iodide. Attach a microscale water-cooled condenser and, after cold water is circulating, heat to reflux directly on a hot plate (medium setting) for 1 hour. Obtain the IR of acetaminophen and work on the abstract or experimental methods during this time. Each student must make an IR sample (nujol mull) and obtain a fresh spectrum of acetaminophen this week (no sharing, there is ample time!). HO H N O CH 3 CH 2 I, K 2 CO 3 CH 3 CN, Δ (^) O H N O Acetaminophen Phenacetin Week 1 (reaction) Week 2 (analysis) KBrO 3 , HAc HBr( aq ) O H N O Br Bromophenacetin Week 3 (reaction, purification, analysis)

Reaction Work Up. Turn off the heat, lift the clamped apparatus, allow the mixture to cool, then add 8 mL of water to the flask. Perform the remainder of this procedure in the fume hood. Transfer the reaction mixture to a screw-cap test tube and use 2 x 2 mL of BME to complete the transfer. Cap, invert, and vent several times before removing the aqueous layer and placing it into a different screw-cap test tube. Extract the aqueous layer with 2 x 5 mL of BME. Remove the aqueous layer into a separate container, discarding at the end of the experiment. Combine the organic layers and extract with 2 x 5 mL of 5% NaOH followed by 5 mL of sat. NaCl. Save the aqueous layers and dispose at the end of the experiment (can combine with aqueous from previous step). Dry the organic layer with minimal MgSO 4 for 5 minutes and filter with a pipet loosely packed with cotton into a dry, pre-weighed 25 - mL RBF (or larger if appropriate). Concentrate using a rota-vap and obtain the crude mass of product (mg and % yield). Eight students in the lab will prepare a sample for 1 H NMR analysis. Before making 1 H NMR samples, TLC should be used to test the product for purity relative to standards (conversion to product and absence of acetaminophen). TLC analysis can be performed in week 2 for the remainder of the class not making NMR samples. Weigh approximately 10 mg of product into a dram vial. Add 800 μL of CDCl 3 , dissolve, then transfer into a labeled NMR tube (initials; section info – day, time, TA; “Phenacetin”), cap, and leave in the designated space per TA instructions. Do not invert the capped NMR tubes! Students will be notified when spectra are available on the course website. Time permitting, obtain the IR of phenacetin and the melting points of both acetaminophen and phenacetin. This can also be completed next week. All students will save the product in the RBF in a vial for next week. Week 2 – Analysis of Phenacetin Ferric Chloride Test for Phenols. Place 1 mL of an aqueous ferric chloride solution (0.1%) in each of three small, labeled test tubes (acetaminophen, phenacetin product, and water). Add a microspatula-ful of the two solids to two of the test tubes and a drop of water to the third. Observe the change in color. Colors ranging from green to red are considered a positive test; yellow is negative. Analysis. Determine the melting points of acetaminophen and phenacetin. Obtain the IR spectrum of phenacetin. Assess purity of the product by TLC (if not completed the week before) and compare to standards of acetaminophen and/or phenacetin. TLC solutions should be made in test tubes using a few crystals of solid in 1 mL acetone. Students are strongly encouraged to work on a draft of the abstract and experimental methods sections before leaving lab this week. Week 3 – Substitution Puzzle: Bromination of Phenacetin Transfer 200 mg of phenacetin and 63 mg of potassium bromate into a 25-mL Erlenmeyer flask equipped with magnetic stir bar. If you have less than 200 mg of pure phenacetin, scale reagents accordingly. Add 2.5 mL of glacial acetic acid and stir to dissolve phenacetin (potassium bromate will not dissolve at this point). Slowly add 0.225 mL of aqueous HBr (48% w/w) drop-wise and stir well during the addition. Continue to stir for 30 minutes at room temperature. The solution should turn orange, indicating the formation of bromine. Proofread your neighbor’s abstract and experimental section during the reaction time. Use a pipet to transfer the reaction mixture to a small beaker containing 20 mL of cold water. Cool the system in an ice-water bath to crystallize the solid. If the solution is still orange, add a

Introduction: Pre-Lab Questions – turn in separate printed responses each week Week 1

Calculate the mmols of each reagent used in the synthesis of phenacetin (excluding the solvent). Determine the limiting reagent. Show your work.
Calculate the theoretical yield of phenacetin. Show your work.
Draw the mechanism for the synthesis of phenacetin from acetaminophen, potassium carbonate, and ethyl iodide.
Why is the reaction mixture extracted with the aqueous NaOH solution?
What are the expected distinguishing IR signals in phenacetin and how do they differ from acetaminophen? Include the functional groups, bonds, and expected ranges. Week 2 Bring the technical writing guidelines to lab this week. Week 3 In addition to pre-lab questions, bring a draft of the Exp 5 abstract and experimental methods with characterization for both reactions (leave xx’s for data yet to be obtained).
Draw the mechanism for the bromination of phenacetin with molecular bromine, including an explanation for the formation of isomeric products.
How will you tell the difference between the two possible bromination products by 1 H NMR? Estimate/calculate chemical shifts of as many or as few H’s as you feel necessary. Also give the expected splitting patterns, including long-range (4-bond) coupling. It will be useful to label the protons on both possible products and refer to those signals in your answer.
What is the molar ratio of HBr and KBrO 3 you will be adding to this reaction? What molar ratio of HBr and KBrO 3 should be used to generate Br 2? Consider equation 1 below and answer assuming HBr is the only source of protons. 6 HBr + KBrO 3! 3 Br 2 + KBr + 3 H 2 O (eq. 1) Answer the same question considering equation 2, where there is an additional acid catalyst. 5 Br-^ + BrO 3 -^ + 6 H 3 O+^! 3 Br 2 + 9 H 2 O (eq. 2) Determine whether HBr or KBrO 3 is the limiting reactant in the formation of Br 2 in the reaction you will be performing and report how many mmol of Br 2 will be theoretically formed.
Calculate and report the theoretical yield of the brominated product.

Results: Post-Lab Questions Work on the pertinent questions each week. The entire results section is due all at once one week after the entire experiment is complete with the rest of the report, however, it is highly recommended that students spread out the work evenly over entirety of this three-week lab.

Report the ferric chloride test results (observations and positive/negative test) as well as TLC results (Rf values for acetaminophen and phenacetin). Comment on these results in terms of the success of the Williamson ether synthesis. This is in reference to disappearance of starting material and presence of product, not yield.
Report and briefly comment the % yield or % recovery for each step (reaction 1, reaction 2, and recrystallization of bromophenacetin).
Report the melting points of each sample (acetaminophen, phenacetin, and crude or recrystallized bromophenacetin). Compare these to literature values, presenting the data in table format. The literature melting points are of pure samples, not crude. Comment on the purity of samples. Can you identify the product of the bromination reaction from this data?
Assign each signal in the 1 H NMR to the protons in acetaminophen, phenacetin, and bromophenacetin using table format. Be sure to include the structures with labels (A, B, C, etc.). Compare to the predicted values and to the starting material, if available. Were each of the products clean/complete?
Based on your interpretation of the bromophenacetin 1 H NMR, which product was formed? Briefly explain your reasoning. Refer to one or two specific peaks to support your answer (“signal A” or “the 1H doublet at 7.0 ppm” for example).
Interpret the IR spectrum of each sample. Present your data in table format (3 separate tables) and use one-to-two sentences to comment on the success of your reactions.
Carefully read through the J. Chem. Ed. papers used to develop the procedures for this experiment (in the References section, p. E5-3). Comment on the changes in procedure of phenacetin synthesis and expected results of the bromination based on these articles. Explain the possible reasons for these changes and rationalize the expected bromination results given your knowledge of trends in EArS reactions.
Search the Journal of the American Chemical Society (pubs.acs.org) for an article with “phenacetin” in the title. Draw the structure of a phenacetin derivative and provide the citation. O H N O N-acetyl-2-bromo- 4-ethoxyaniline mp 96-97 oC O H N O N-acetyl-3-bromo- 4-ethoxyaniline mp 112-114 oC Br Br

Exp 5 – Synthesis and Bromination Name _____________________________ Of Phenacetin Section Day _____ Time _____ TA Name __________________________ CHEM 110L Formal Lab Report SECTION INSTRUCTOR COMMENTS POINTS ASSIGNED IN-LAB QUIZZES / 10 ABSTRACT One paragraph, 6 - 10 sentences: Purpose, procedure, main result(s), and conclusion(s). / 20 INTRODUCTION Original responses to pre-lab questions with TA initials / 60 RESULTS The main results are stated, as outlined in the post-lab questions, using complete sentences. / 50 EXPERIMENTAL SECTION The experimental details (including final amount used and obtained) are briefly described in a few sentences. Compound characterization included. / 25 NOTEBOOK PAGES Proper format: reaction scheme, chemical info table, procedure, waste and clean-up procedure. / 50 NEATNESS AND ORGANIZATION Proper order and format (see syllabus for full descriptions of each section). / 25 REASONABLE DRAFT of the abstract and experimental section brought to week 3 of lab, attached to the report, revisions made. / 10 LAB REPORT TOTAL / 250

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