Liam Springer, Liam Doyle, and Wiley Turner

Packer Collegiate Institute, 170 Joralemon Street, Brooklyn, NY, 11201

Submitted January, 13 2017

Introduction:

Since the dawn of civilization, humanity has searched for the ultimate panacea for pain.

One remedy for this has been salicylic acid. The pain relieving uses of salicylic acid have been

known to people for thousands of years, ever since healers in ancient China used willow bark to

quell pain. Unfortunately, the side effects of salicylic acid include stomach irritation and ulcers. It

was not until the 19th century when the German chemist Felix Hoffmann successfully

synthesized acetylsalicylic acid. Acetylsalicylic acid, colloquially referred to as aspirin, is a

compound that possesses the same pain relieving benefits of salicylic acid, but without the

unpleasant side effects. Acetylsalicylic acid has become one of the most commonly used

medicines in the entire world, and, in America alone, 27 billion tablets are consumed each year.

The possibility of taking a slice of this large market may seem tantalizing, but the right synthesis

is required. Let us guide you down the path to profits.

We created acetylsalicylic acid through the esterification reaction of salicylic acid and

acetic anhydride. This reaction yielded our desired product, acetylsalicylic acid, as well a

byproduct, acetic acid.

Figure 1: Diagram of the esterification reaction between salicylic acid and acetic anhydride
producing acetylsalicylic acid and acetic acid

1
As seen in figure one, there are two bonds that break in this reaction. The first bond that breaks

is between the OH (blue), originally connected to the carbon chain in the salicylic acid, and

between a carbon bonded to the central oxygen (red) in the acetic anhydride. The hydrogen

separated from the salicylic acid (blue) attaches to the single bonded oxygen of the acetic

anhydride, while the carbon double bonded to oxygen (red) attaches to the single bonded

oxygen of the salicylic acid. The molar ratio of this reaction is 1:1:1:1, meaning that a mole of

each reactant will theoretically yield a mole of each product. In order for this reaction to take

place, both reactants must be dissolved in a solution (ie. water), and a catalyst (ie. phosphoric

acid) needs to be present. Once the products are attained, it is relatively easy to separate most

of them. After the reaction, water is added in order to react with the excess acetic anhydride,

forming additional acetic acid. After the aspirin sample is crystallized, it can be separated from

the acetic acid and phosphoric acid through vacuum filtration. After filtration, you are then left

with a semi-pure sample of acetylsalicylic. The only problem is that this aspirin could also

contain salicylic acid, which is much harder to separate.

We would first like to introduce you to some essential techniques in our process. The

main method we used to refine this sample of aspirin was recrystallization. Recrystallization is a

technique for purifying a solid, and it uses the different solubilities of different molecules in a

sample. When a solvent is poured on the sample and the flask is heated gradually, the solids

should dissolve into it. Then, as the solution is slowly cooled in an ice bath, the less soluble

substance should recrystallize while the more soluble substance remains dissolved. After this,

the sample created needed to be analyzed for purity. This was done in two ways. Colorimetry

and melting point testing. Colorimetry works by testing the absorbance for a certain wavelength

of light through a solution. The darker the solution, the higher the absorbance value. In our

2
testing, we created a solution of iron (III) nitrate and our asprin sample. The iron (III) nitrate

bonded to the salicylic acid remaining in the solution and formed a dark purple solution. The

lower the amount of salicylic acid, the less purple the solution would be. These absorbance

values were then compared to a line of best fit of 4 absorbance values of known solutions with

different concentrations of salicylic acid. This comparison showed us the relationship and from

there, we were able to find the molarity of the salicylic acid in our sample. Furthermore, melting

point testing uses a substance's melting point. The recovered sample can be placed in a Vernier

Heat Station and can be observed as the temperature slowly increases. The range at which the

substance melts can be tracked, and it can then be compared to the melting point of what the

substance is supposed to be. If the substance has a similar melting range as the expected one,

then it most likely is, but if the range of the recovered substance is greater than 2C and non

similar, it indicates that the substance is, in fact, impure.

Our Procedure:

4.60 grams of salicylic acid were initially weighed, and 9 mL of acetic anhydride was

subsequently measured. The salicylic acid was then poured from the weigh boat into a 250 mL

Erlenmeyer flask. Any clumps of salicylic acid observed in the Erlenmeyer flask were then

crushed up. Then, 2 mL of the measured acetic anhydride was poured into same weigh boat

that was used to measure the salicylic acid in order to wash off the remaining solid. This liquid

was then added to the Erlenmeyer flask, along with the rest of acetic anhydride. Tap water was

then poured into a 500 mL beaker and placed on a hot plate. A ring stand was positioned next

to the hot plate, and the Erlenmeyer flask containing the two reactants was attached to it. When

the water bath reached around boiling, the Erlenmeyer flask was placed inside. Directly after, 10

drops of 6M sulfuric acid was added to the Erlenmeyer flask. A stir rod was then placed into the

3
Erlenmeyer flask and the stir feature on the hot plate was turned on. After twenty minutes, or the

point when vapors were no longer released, the Erlenmeyer flask was removed from the boiling

water. The stir rod was then also removed, and the flask was placed on a hot pad. The flask

was then allowed to cool for three minutes. After the cooling period, 15 mL of room temperature,

distilled water was then added to flask and the solution was swirled. The solution was then

further cooled to allow for it to reach room temperature. The flask was then placed in an ice bath

to crystallize.

After crystallization, the solution was transferred to a Bchner funnel assembly. The filter

paper was then moistened with distilled water, and the solution was vacuum filtered. Then, cold,

distilled water was used to ensure that all of the solution had been removed from the

Erlenmeyer flask. After all the solution had been emptied from the flask, and no more liquid was

being filtered out, the vacuum was gently broken. This vacuum was then recreated, and the

crystals on the filter paper were washed with 5 mL of cold, distilled water. This process was then

repeated two more times. The filter paper on which the crystals laid was removed, and it was

replaced with a new filter paper (which was moistened by a minimal amount of distilled water).

The vacuum filtration process was then repeated with the filtrate except without breaking the

vacuum or washing the crystals. After this step, 18 mL of ethanol was measured as well as 39

mL of distilled water. A new 250 mL Erlenmeyer flask was also added. The maximum amount of

crystals that could be transferred from the two filter papers were then placed in the new

Erlenmeyer flask. A funnel was then placed in the Erlenmeyer flask as well. Each piece of filter

paper was held right above the funnel by a pair of tweezers. Then, 14 mL of ethanol was poured

onto the first filter paper (and fed through the funnel). The was same process was then repeated

with the second filter paper using the remaining 4 mL of ethanol. The funnel was then removed

from the flask and any large clumps of crystals were broken up using a stirrer. The solution was

4
then swirled thoroughly. Because not all the crystals had dissolved, the flask was placed on a

hot plate and tepidly warmed. After the crystals were completely dissolved in the ethanol, the

flask was removed from the hot plate and 39 mL of water was added. The solution was allowed

to cool until it reached room temperature, and then placed in an ice bath to allow for

recrystallization.

After the crystals had formed, a Bchner funnel was assembled. Vacuum filtration was

then carried out using the identical procedure as explained previously. The recovered solid was

transferred to a watch glass and allowed to dry in the drying oven for fifteen minutes. After they

were dried, the recovered substance was massed.

To test purity through colorimetry, 0.40 g of the recovered aspirin sample was

transferred into a 250 mL beaker along with 10 mL of 95% ethanol. The beaker was swirled until

the solid aspirin sample was dissolved.105 mL of distilled water was then added to the beaker

and the solution was thoroughly mixed. The solution was then transferred from the beaker to a

250 mL volumetric flask. The empty beaker was rinsed several times with distilled water, which

was then transferred to the volumetric flask. Additional distilled water was then added to fill the

flask to the 250 mL mark. The solution was then mixed thoroughly.

5.0 mL of the aspirin solution was transferred from the volumetric flask to a clean 100 mL

volumetric flask. Then, 0.025 M Fe(NO3)3 was added to fill the flask to exactly 100 mL. The

absorbance of the treated aspirin sample was then recorded by filling a cuvette full and

placing it in the spectrometer. This process was repeated twice more with new aliquots of the

treated aspirin sample.

After the absorbance had been collected using the spectrometer, the melting point

temperature was collected using Logger Pro and the Vernier Melt Station. To find the melting

point, 3-4 millimetres of acetylsalicylic acid was collected using a capillary tube, which was then

5
placed in the Melting Station. The melting point temperature range was collected by recording

the temperature when the aspirin initially melted to the point where it was fully melted.

Explanation of The Procedure:

Now, we would like to walk you through the details of this procedure. A point of much

significance is the amount of each reactant used. We wanted salicylic acid to be the limiting

reagent due to it being harder to separate from the acetylsalicylic acid then acetic anhydride

(the other reactant). We then set the theoretical yield of acetylsalicylic acid to 6.00 grams to

ensure the required production of 2.92 grams. To produce a 6.00 gram theoretical yield, we

needed 4.60 grams of salicylic acid. We then decided upon the amount of acetic anhydride we

would need to add, and we ultimately decided to add 9 mL. It is important to note that because

the reaction between salicylic acid and acetic anhydride is one to one, only 3.78 mL would,

hypothetically, be required to efficiently run the reaction. We decided to add a large excess of

acetic anhydride in order for it to act as the solvent. Originally, water was used as the solvent,

but the only problem is that water reacts with acetic anhydride to produce acetic acid. If this

reaction takes place before the all of the salicylic acid has be reacted, there will be an excess of

salicylic acid. The amount of acetic anhydride necessary to completely react with the water

solvent and all of the salicylic acid is an infeasible amount (of 27 mL). By using water as the

solvent you allow for a sizable amount of salicylic acid to remain after the reaction. Instead, we

decided to attempt using acetic anhydride as the solvent, as well as the reactant. Our data is

shown below in figure two. The use of acetic anhydride as the solvent led to an 8.3% reduction

in the salicylic acid making up the total sample. It is also important to point out that the addition

Data Table Comparing The Solvent Used During The Reaction to The Percent of Salicylic
Making up final sample
Solvent Used During Reaction Percent of salicylic acid making up total

6
 sample (%)

distilled water 20%

acetic anhydride 10.7%

Figure 2: Percent of salicylic acid present in sample using different solvents

of 5 mL of acetic anhydride to act as the solvent was an arbitrary amount that could be further

tested to discover how it could be changed to reduce cost or to increases the purity of our

sample. We used the acetic anhydride to wash out the remaining salicylic acid in the weight

boat. This was done to ensure that we used all of the salicylic acid in the reaction. After the

reactants were added to the Erlenmeyer flask, we crushed up any clumps of salicylic acid. By

maximizing the surface area, we increased the rate at which it reacts with the liquid acetic

anhydride. After this step, we added 10 drops of sulfuric acid to the Erlenmeyer flask. The

reason we used sulfuric acid instead of phosphoric acid was due to the data we collected after

completing trials with different catalysts. The sample with sulfuric acid had an Rf value
of greater

similarity to acetylsalicylic acid than that of pure salicylic acid (as shown in Figure three).

Data Table Showing Relationship between Rf values

of Our Recovered Samples (with different
catalysts being used) and the Rf value
of known Substances

Pure Pure salicylic Recovered Recovered

acetylsalicylic acid aspirin sample aspirin sample
acid (using sulfuric (using
acid) phosphoric
acid)

Rf value
of 0.69 0.51 0.67 (streak) 0.56 (streak)
sample
Figure 3: Comparison between Rf values
of recovered samples (with different different catalyst
be used) and pure acetylsalicylic/salicylic acid

7
Our data indicates that there was more acetylsalicylic acid, and consequently less salicylic acid,

present in the reaction performed with sulfuric acid as the catalyst than phosphoric acid.

We then heated the Erlenmeyer flask using a water bath. The reason we did this was to evenly

distribute heat throughout the Erlenmeyer flask. This is important because it ensures all

reactants have the necessary activation energy to react. It is also important because it ensures

that certain molecules are not overheated to the point where they decompose. We made sure to

stop the reaction after the release of vapors ceased (indicating the completion of the reaction),

but ultimately decided to stop the reaction at around twenty minutes. This was an arbitrary

distinction as it is very hard to tell when vapors had completely stopped being produced. Thus, if

our procedure is chosen, we would test further in order to maximize the efficiency and purity of

this procedure. We then let it cool to room temperature and then added distilled water to the

solution. The distilled water was added so that it would react with the remaining acetic

anhydride to produce acetic acid. The reason we waited until the solution cooled before adding

the water, was to minimize the amount of acetylsalicylic acid that dissolved into the water. We

then placed the flask in an ice bath to achieve recrystallization. Cooling the solution too quickly

can result in impurities crystallizing with the desired product. By allowing the solution to cool to

room temperature, and then adding to the ice bath allowed for pure, high quality crystals to be

formed.

Just like the original procedure, the product was isolated by vacuum filtration. We

washed out all of the product from the Erlenmeyer flask using cold, distilled water. The crystals

were then washed three times with cold, distilled water. The reason the crystals were washed in

the first place was to clean them of the acetic acid, or other impurities. We used cold water

throughout the filtration process to minimize the amount of acetylsalicylic acid that would

dissolve into the water, this helps to maximise the percent yield of the procedure. After the

8
vacuum filtration was completed we noticed that a small amount of crystals appeared to have

gone through the filter paper and into the waste flask. Thus, we decided to repeat this process

with the waste flask in order to maximize the recovered amount of acetylsalicylic acid possible;

but with that said, we didnt wash them with cold, distilled water (like we did for the original

sample) because we didnt feel it would be cost effective.

We then recrystallized the total recovered aspirin sample to increase the purity. We did

this by first placing all of the sample into a new Erlenmeyer flask. We then installed a funnel into

the flask and washed 18 mL of ethanol onto the filter paper to ensure that all of the sample was

transferred. We figured that the ethanol would dislocate any of the recovered sample from the

filter paper and wash it down into the Erlenmeyer flask. Ethanol was used as one of the solvents

for recrystallization. We broke up any clumps of the sample in the new flask, to increase the

speed it dissolved into the ethanol. We also heated the solution using a hot plate to increase the

rate at which the sample dissolved. After the aspirin sample had dissolved, we removed it from

the hot plate and added water (which is more polar than ethanol) to increase the polarity of the

overall solution. The goal was to increase the polarity of the overall solvent gradually, similar to

decreasing the temperature gradually when crystallizing a solid improves purity; it would

improve the overall usefulness of the recrystallization process. We then waited for the solution

to return to room temperature to, once again, increase the cooling rate of the process. After it

cooled to room temperature, we then transferred the flask to an ice bath to allow the crystals to

form. In the future, we would like to investigate how different ratios of water and ethanol affect

the overall efficiency and effectiveness of the recrystallization process. As seen in figure four,

recrystallization did have a meaningful effect on the purity of our recovered aspirin sample as it

reduced the percent of salicylic acid making up the total sample by 3.9%; but, the fact that it

only

9
Data Table Showing the Difference in Percent of Salicylic Acid Making Up the Total Sample in a
Recrystallized Sample and a Non-recrystallized Sample
Purification Technique Percent of salicylic acid making up total
sample (%)

Recrystallized 6.8%

Not recrystallized 10.7%

Figure 4: Percent of salicylic acid making up total sample in trials with and without the use of
recrystallization

reduced it by that much also suggests that there is much room for improvement, and thus, the

purity of the aspirin sample it created. After the recrystallization, we performed vacuum filtration

once more to isolate the crystals and, just like the vacuum filtration for the initial sample, we

employed all the same techniques for all the same reasons. We then took the recovered

crystals and dried them for 15 minutes. Then, the recovered solid was weighed using a scale

and tested for purity using colorimetry.

How We Plan to Improve Our Procedure:

Though our procedure was highly improved from the baseline test, there are also many

things that we can still improve upon to increase our percent yield, percent purity, and cost

effectiveness. One example of this is to upgrade our equipment. In our testing, we often found

that lots of substance would be attached to either the filter paper, funnel, or weigh boat. Even

though we took steps to mitigate their effects, it was an inevitable problem simply based on the

tools at our disposal. Though we did devise a strategy to get the salicylic acid off of the weigh

boat (by pouring acetic anhydride onto the weigh boat to rinse off left over salicylic acid), there

were still many steps where we found ourselves wondering how to get substance off of our

tools. The part where we lost a significant amount of our sample was during filtration using the

Bchner funnel. The filter paper covered most of the funnel opening, but there was a slim edge

10
where there was no paper. A fair amount of our sample was left on that edge after filtering

resulting in lost aspirin crystals. With a more professional setup and an investment of capital, we

would be able to recover a much higher percent of our produced aspirin sample.

We believe that the recrystallization process is a point where much improvement could

be made. Although it helped to increase the purity of our recovered sample 3.9% (leading to a

final sample of 93.4% purity), we feel like the effectiveness of the process could be optimized

through further trials. For example, the ratio of ethanol and water added to recrystallize the

sample is something that could very easily be more thoroughly investigated to increase the

effectiveness of the recrystallization. Another improvement that could be made would be to

recrystallize our aspirin more than once. By repeating the recrystallization process, the purity of

the recovered substance will further increase (by less and less each additional time), allowing

for a more viable percent purity.

We could also improve the reaction itself. An example is the amount of each reactant

used. We were pressed for time, making it impossible for us to test different ratios of reactants.

We believe that with more testing, we would be able to perfect this ratio to make the reaction

even more efficient and profitable. This ratio could then be scaled up to the industrial size. With

all of these changes and the new ideas that will inevitably arise with more research, we believe

that our aspirin can become a major competitor in the aspirin market giving LuChem opportunity

to become the new Bayer.

Why We Should Be Chosen:

Despite our original procedure only yielding 29% and having a purity of 78%, we were

able to drastically improve our method. Our final procedure resulted in a yield of 78.3 % and a

purity of 93.4 %. This percentage corresponds to an actual yield of 4.60 grams compared to the

11
6.00 grams of theoretical yield. Our purity value corresponds to 4.29 grams of acetylsalicylic

acid out of 4.60 grams of our total sample. This 93.4 % purity was confirmed by the melting

point test which showed that our sample had a melting range of 135.3 - 136.7 (figure 5).

A Graph Showing the Experimental Melting Range of our Recovered Aspirin Sample

Figure 5: The melting point graph for our final sample of aspirin. The final melting range
of this sample was 135.3-136.7, very close to the 136-138 melting range of pure
acetylsalicylic acid.

Our synthesis has the potential to produce unfathomable wealth, which will transform LuChem

into one of the largest and most profitable pharmaceutical companies in the United States. Our

synthesis also has the potential to improve its percent purity, yield, and profitability from its

already satisfactory and profitable numbers. The total cost for our production of one hundred

boxes of 36, 81 mg pills is $224.43. This price includes the cost of labor in Wyoming, where the

minimum wage is a measly $7.25. In our factory, we would pay workers $8.00 an hour which

would create motivation work ethic as they have more to lose than just another minimum wage

job (figure 6).

12
 Resource Cost List
Resource Cost per unit Amount Needed to make Cost to
100 pkgs Produce
acetic $37.70/L 0.558 L $21.0
anhydride
6 M sulfuric acid $0.001305/drop 620. drops $8.09

salicylic acid $42.00/kg 2.85 kg $120

distilled water $2.00/L 7.34 L $14.7

ethanol $12.5/L 1.12 L $14.0

0.1 M iron (III) $13.10/L 0.095 L $1.24

nitrate
small hot plate $0.30/hr (1.5 kW/h, $0.20/kWh) 1 hour $0.30

filter paper $0.05/sheet 62 (estimated) $3.10

labor (minimum Currently $5.15/hr, really 2 people $32.00

wage) in the $7.25/hr (federal minimum 2 hours
state of wage)
Wyoming
We are paying our workers
$8.00
Total Cost $214.43

Figure 6: A table showing the costs of our reaction scaled up in order to make 100
aspirin packages.

Along with a low minimum wage, Wyoming also has a high unemployment rate of 4.1 %. This

rate means that there will be an abundant supply of workers looking for jobs, decreasing the

difficulty of finding labor. Land in Wyoming is also inexpensive, the average price for an acre of

land costs $1,558.

Our Profits for 100 Packages at Different Price Points

Number of 36 tablet Cost of Price Per Unit Total Profit Percent
(81 mg) boxes of Production (Box of Margin* Profit
aspirin product)

13
 100 $214.43 $3.29 (Bayers $329.00 $114.57 53.4%
price)

100 $214.43 $2.99 $299.00 $84.57 39.4%

Figure 7: A table showing the profit of 100 packages of our aspirin at two different price
points.

*Labor is included in cost, this is our profit after all expenses

The cheap cost of land means that building a large scale factory would be easy and cost

effective. This shift of location would save lots of money both in the short run and long run. If we

were to sell 100 boxes of LuChem aspirin for $2.99, our profits would be $84.57 (a 39.4 %

profit). If our yield were to increase to 95 %, which we believe is very feasible with more time

and better manufacturing tools, we would make $114.57 resulting in a 53.4 % profit (up from

39.4 % with a 78.3 % yield)(figure 7). This data shows the potential for significant profit with our

procedure. On top of this, as our synthesis is further industrialized, profits will continue to grow

as the margins will continue to widen. Along with our competitive price point and profitable

margins, our aspirin is also more innovative than any other aspirin proposed to the board of

investors. This aspirin synthesis technique can take LuChem further than any other, and we

hope you see it that way too.

Thank You,

Liam Doyle, Wiley Turner, Liam Springer

X_______________________________

14
 X_______________________________

X_______________________________

References

Frohlich, T. C., & Kent, A. (2015, June 05). Americas Most (and Least) Valuable States.
Retrieved January 12, 2017, from
http://247wallst.com/special-report/2015/06/03/the-most-and-least-valuable-states/11/.

Neal, R. (2004, February 10). World's Wonder Drug. Retrieved January 11, 2017, from
http://www.cbsnews.com/news/worlds-wonder-drug/.

Piscean. (n.d.). Synthesis of Aspirin. Retrieved January 13, 2017, from

http://medicinal-chemistry-notes.blogspot.com/2011/09/synthesis-of-aspirin.html.

Synthesis of Aspirin. (n.d.). Neonatal Formulary. doi:10.1002/9780470750872.ch27.

Wyoming. (n.d.). Retrieved January 12, 2017, from

15
https://www.minimumwage.com/in-your-state/wyoming/.

16