Experiment 3 Synthesis of Acetaminophen PDF

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Summary

lab report for synthesis of acetaminophen...

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Experiment 3: Synthesis of Acetaminophen Sophia Olvera February 27, 2021 Section: AA purpose The purpose of this experiment is to synthesize acetaminophen. Once synthesized, the purity of the acetaminophen will be tested by performing melting point determination. reaction and synthesis

In this experiment, p-aminophenol is treated with acetic anhydride; followed by recrystallization to produce a crude acetaminophen. Proceeded by decolorizing the acetaminophen by treating the mixture with sodium dithionite and heating. The product is further purified by a second recrystallization using a 50/50 water methanol solution. Once prepared, the crude and final synthetic product will be analyzed via melting point analysis and compared to literature value melting point. [Acetaminophen melting point: 169.5-171 °C]. The experimental percent yield and purity of the synthesized acetaminophen are of most importance mainly for financial and logistical reasons. When synthesizing one of the most commonly used drugs in the country, it is crucial to continuously produce results of a high (90%+) yield. This is because you want your production scheme to be as efficient as possible. If the mass production of acetaminophen results in a 20% yield, you may still produce product but at the cost of precious time and money therefore percent yield is very important for pharmaceutical companies trying to produce the largest yield with the least waste. In terms of purity of product, a lower percent yield indicates the reaction might be producing unwanted byproducts. Understanding what part of the experiment, more specifically the reaction, can be fixed by using a limiting volume of certain reagents, in turn increasing the purity of the product.

table of reagents

Name / Formula p-aminophenol C6H7NO acetic anhydride C4H6O3 or (CH3CO)2O

sodium dithionite (sodium hydrosulfite) Na2S2O4 methanol CH3OH (l) acetaminophen (paracetamol) C3H9NO2 or HOC6H4NHCOCH3

MW (g/mol)

Density (g/ml)

Amount

109.13

1.13

0.150 g

mp 187.5 °C

102.09

1.08

0.165 mL

bp 139.8°C mp 73.1°C

174.107

2.38

0.2 g

mp 52 °C

Flammable, Irritant

32.04

0.791

bp, 64.7℃

Flammable, Irritant, Solvent

151.16

1.3

bp, 420°C mp, 169.5171°C

Pharmaceutical, Hepatotoxic Common Name: Tylenol

0.208*

Physical Constants

Hazards Irritant, Health Hazard, Environmental Hazard Flammable, Corrosive, Irritant

*Acetaminophen produced in synthesis should have a theoretical yield of 0.208g.

procedure

data & observations

reaction mixture and synthesis 1. Weigh out ~0.150g p-aminophenol and transfer to a 5 mL conical vial. 2. With a graduated pipet, add 0.450 mL water and 1.165 mL of acetic anhydride. 3. Place a spin vane and attach to the air condenser. heating 1. Begin heating the reaction mixture with an aluminum block or sand bath around 120°C(248°F) while gently stirring. Note: The conical vail should be buried partially in the sand, almost touching the bottom of the tin bath. 2. While waiting for solid to dissolve, keep

p-aminophenol initial mass: 0.151g p-aminophenol initial mass: 0.155g total water used: 0.500mL total water used: 0.500mL total acetic anhydride used: 0.178g, liquid was massed instead of using volume total acetic anhydride used: 0.180g, liquid was massed again instead of using volume.

in mind that the solid may dissolve, form a precipitate, and re-dissolve. Due to this behavior, it is crucial to observe carefully. 3. After the solid has dissolved, heat the mixture for another 20 minutes. This will ensure the reaction is pushed to completion. isolation of crude acetaminophen 1. Once the additional 20 minutes have passed, remove the vial from the heating source and allow it to cool. 2. As the vial is cooled to the touch, carefully detach the air condenser and remove the spin vane with clean metal forceps or clean magnet. 3. Rinse the spin vane with 2-3 drops of warm water, allowing the rinse to drop into the conical vial containing the crude acetaminophen. Then place the conical vial within a 25-mL beaker and allow it cool to room temperature. Record your observations as crystallization begins to occur. o If crystallization has yet to occur, take a glass stirring rod to the sides of the vial and gently scratch. This will induce crystallization. 4. Transfer vial to an ice bath to further cool for an additional 15-20 minutes. 5. Begin the collecting process by correctly setting up the filtration system. Do not forget paper filter. 6. Rinse the vial with 0.5mL of ice water and transfer contents to a Hirsch funnel. 7. Wash the crystals two additional times with a 0.5mL portions each time. 8. Dry the crystals for 5-10 minutes using the vacuum and funnel. 9. Carefully transfer the crude product to a pre-weighted watch glass allowing them to continue drying. 10. Weigh and record mass crude product. 11. Place enough crude product into a capillary tube for melting point analysis. 12. Record the appearance of the crystals. 13. Calculate the percent yield of crude acetaminophen.

rxn mixture heated for additional 17 minutes at a consistent heat of 120°C rxn heated for 17 minutes with a fluctuating temp. ranging from 110-130℃ o there was a decrease in temperature twice as the rxn was pushing towards equilibrium > indicative of an endothermic reaction. as the conical vial pulls heat from the san bath, the sand itself is losing heat resulting in systematic heat loss.

observation: the vial was cool to the touch almost immediately after removing from heat. observation: vial was cool to touch almost immediately after lowering big jack and removing heat. due to fluctuating temp., solution mixture has darkened; color changed from light sand to a dark chocolate. observation: crystallization has begun; crystals in current mother liquor have the appearance of sand granules. most of the crystallization of crude acetaminophen was noticed prior to placing in ice bath. observation: crystallization has begun; crystals are hard to see due to darkened mother liquor. observation: after 17 minutes in the ice bath, the crystals are much more prominent, however the crystals still take on the appearance of granular sand. observation: conical vial cooled in ice bath for a total of 20 minutes. crystals now much more prominent as they continue to collect at the bottom of the conical flask.

(my) mass isolated product: 0.039g (25.83%) mass product of gifted product: 0.051g (34.0%) total mass isolated product: 0.090g melting point determination: 147-150 °C isolated product formed crystals containing a beige, almost chocolate tint. perhaps due to the fluctuation in temperature.

decolorization of crude acetaminophen 1. In a 5 mL conical vial, dissolve 0.2g of sodium dithionite, aka sodium hydrosulfite, in 1.5 mL of water and add crude acetaminophen to the vial. 2. Heat the mixture at ~100° C(212°F) for 15 minutes with occasional stirring using a micro spatula or stirring bar. o It is possible for a small amount of acetaminophen to dissolve. 3. Take the vial off the heat source and let cool in an ice bath for ~10 minutes. 4. Collect the purified acetaminophen atop the Hirsh funnel and begin filtration process. 5. Allow the crystals to dry for 5-10 minutes. 6. Weight and record the mass of the pure acetaminophen. 7. Compare observations of the isolated product vs. the crude product. crystallization of acetaminophen 1. Place purified acetaminophen in craig tube. 2. In a separate test tube, heat a mixture composed of 50% water and 50% methanol by volume at ~100°C(212°F). [Try to use 2/3mL total for solvent]. Make sure to add a boiling chip before heating if provided. 3. Add hot solvent into the craig tube dropwise until the solid dissolves. 4. Once dissolved, rest the craig tube in a 10mL Erlenmeyer flask and insert the inner plug. 5. Let the solution cool. Observe as crystallization occurs. 6. With acetaminophen at room temp, transfer the craig tube into an ice bath to cool more thoroughly. o If crystallization has yet to occur, take a glass stirring rod to the sides of the vial and gently scratch. This will induce crystallization 7. Continue cooling for at least 10 minutes. 8. In order to collect the crystals, we must centrifuge the craig tube as we would like

percent yield isolated product: 59.83%

mass crude product: 0.034g percent yield crude product: 37.78% isolated crystals appeared darker while crude crystals were much lighter, almost pink in color. in addition to color change, crystals from isolated product took on the appearance of a coarse powder while crude product produced a more defined shiny crystal structure.

to remove mother liquor 9. To prepare for centrifuging, hold the tube vertically and plug the top of the tube with the thicker side of the plug, copper wire should be closer to the plastic centrifuge tube. Once assembled, flip the whole craig tube upside down and insert it into the centrifuge. Note: The craig tube with crystals should be on the top now. o Proper usage of the centrifuge instrument calls for another equally weighing craig tube be assembled and inserted in order to balance the centrifuge. 10. Turn on the centrifuge for 3-5 minutes at 2000rpm o Check on crystals; if mother liquor still remains in the craig tube, centrifuge or another 2 minutes. 11. Having successfully separated the mother liquor from our crystals, pull the centrifuge tube out of the instrument. Once in hand, carefully pull the copper wire up simultaneously holding onto the inverted craig tube > this is where the crystals are located! Make sure to not lose your newly formed crystals! 12. Transfer the product onto a pre-weighed watch glass or a new piece of sample paper; let sit to continue airdrying. yield calculation and melting point determination 1. Weigh the crystallized acetaminophen and calculate the percent yield. 2. Determine the melting points of both the crude and purified products via melting point analysis and compare. 3. Compare the colors of the crude, decolorized and pure acetaminophen. 4. Place product in a properly labeled vial and submit to instructor.

mass crystalized acetaminophen: 0.010g percent yield crystallized acetaminophen: 29.4% melting point determination: 165-168°C isolated crystals appeared darker while crude crystals were much lighter, almost pink in color. the pure acetaminophen crystals appeared an off-white creamy color.

table of results recovered mass (g)

% yield

isolated C3H9NO2

0.090

59.83%

crude decolorized C3H9NO2

0.034

37.78%

pure crystallized C3H9NO2

0.010

29.4%

discussion During the first isolation of crude product, there was difficulty in stabilizing the temperature of the sand bath. The unstable temperature is thought to have caused the reaction mixture to darken to an opaque mocha color. Once filtered, the crystals still appeared somewhat powdery but significantly lighter in color. Still the crude product had been tinted brown. At such an early point in the experiment, the yield had already appeared so low and resulted in a mass of 0.039 grams. The synthesis had only yielded 25.83% of the desired product. With the product having significantly reduced, 0.051 grams of isolated product had been given by another student who could no longer proceed with the experiment. This resulted in a total mass of 0.090 grams of isolated product. After decolorizing a second time, the crystals seemed to have a pink tint. Roughly 38% of the decolorized product was yielded. The product had been significantly reduced making it unreasonable to continue. g of decolorized product There was also speculation as to whether or not the acetic anhydride had expired. After a rough experimental process, the purified product weighed in at g, the final crystallization yielding a total of % product. The purity of this product was checked via melting point analysis and compared to that of the crude product. The crude product began to decompose within 165-167 °C, while the purified acetaminophen melted within 167-170 °C. The literature melting point of acetaminophen is recorded at 169.5-171 °C. With a lower melting point, it is evident that our purified product still contains an unknown amount of impurities. The yield and purity discrepancies were due to not monitoring the reaction mixture carefully. There were many faults in the technique and system setup that led to temperature fluctuations, and mishandling glass wear. post-lab questions 1. During the crystallization of acetaminophen, why was the mixture cooled in an ice bath? Before cooled in an ice bath, the purified acetaminophen must cool to room temperature. As the temperature slowly decreases, crystallization begins. Most of the crystallization will occur during this phase and before transferring the craig tube to cool in an ice bath. Transferring the mixture to the ice bath is done to promote the formation of larger crystals. Allowing product to slowly crystallize increases the yield. 2.

In the reaction between p-aminophenol and acetic anhydride to form acetaminophen, 0.450 mL of water was added. What was the purpose of the water?

In the reaction between p-aminophenol and acetic anhydride, 0.450 mL of water was added as a solvent to aid in dissolving the starting material.

3.

Why should you use a minimum amount of water to rinse the conical vial while transferring the purified acetaminophen to the Hirsch funnel?

Acetaminophen is slightly soluble in cold water therefore in order to reduce the amount of product that gets dissolved, it is crucial to use a minimal amount of water. 4.

If 0.130 g of p-aminophenol is allowed to react with excess acetic anhydride, what is the theoretical yield of acetaminophen in moles? In grams?

If 0.130g of p-aminophenol is allowed to react with excess amount of acetic anhydride, the theoretical yield of acetaminophen results in 0.0012 moles or 0.181g acetaminophen. 5.

Give two reasons, why the crude product in most reactions is not pure. o o

Some amount of the starting reagents will remain in the reaction mixture even after reaching completion. There might be an un-wanted impurity within the crude product.

For this particular experiment, the tinted appearance of the crude product visually indicates that there is an un-wanted impurity within the product. Before proceeding straight to crystallization, we proceed decolorizing the crude product with the help of sodium dithionite. 6.

The crude acetaminophen most likely had a dark colored impurity. What would cause the product to be discolored?

The crude acetaminophen contains a dark colored impurity that has gone through the process of oxidation. 7.

Why was sodium dithionite (sodium hydrosulfite, Na 2S2O4) added to the crude acetaminophen? Be more specific!

The sodium dithionite contains the dithionite ion which is known as a reducing agent. As the reducing agent, the dithionite reduces the oxidated impurity responsible for the darkened color of

the crude product. The sodium dithionite is added to the crude product in order to further isolate and purify the acetaminophen. Once heated, the sodium dithionite is breaks apart the bonds of the impurities. Once bonds have been reduced, the decolorized acetaminophen emerges, now ready for filtration....