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Greening the Synthesis and Analysis of Aspirin

by:
Alicia DeLuca (anm7@unh.edu) and Lisa Holt (lvc6@unh.edu)

working with:
Mary Daly, Teacher
Bishop Guertin High School, Nahsua NH





What is Green Chemistry?

Green chemistry is a way of looking at the way that we use chemicals.

Until recently, chemistry has focused on minimizing human exposure to the harmful effects of toxic chemicals through the use of various controls and protective equipment. This has included using protective clothing, eye protection and gloves; and equipment such as fume hoods and special disposal containers and services. While these measures do help to reduce the risks of exposure, they do not eliminate them, and the risk remains for severe exposure in the event of an accidental spill or equipment malfunction.

Green chemistry turns this equation around and asks what can be done to prevent or reduce the need to protect humans and the environment from chemicals and their production in the first place. If toxic chemicals are not being used or produced to begin with, the need to employ protective measures is reduced or eliminated.

To guide chemists in “greening” chemistry, the twelve principles of green chemistry were developed. Using these principles, several approaches have been used to reduce the hazards associated with chemicals. The first has been to attempt, as best as possible, to quantify the actual risks for harm posed by the chemicals. To this end, the “Toxics Release Inventory” ( TRI )has been established to track the reported release of some 300 compounds that are known to be associated with acute health risks. This data gives us some sense of the scale of harmful chemicals being released, though the information is limited to the chemicals on the list, and to TRI-reporting companies. Quantifying the type and degree of risk associated with chemicals is another way to establish a platform from which to determine which chemicals are safe enough to use or to substitute for the more hazardous chemicals, and Materials Safety Data Sheets (MSDS) is a standardized way of communicating this information.

The next step is to look at the actual reactions in terms of the starting materials (“feedstocks”); the solvents, reagents and catalysts used; energy inputs; and byproducts; and to determine the safety and efficiency of the various components as well as the overall reaction. Can a hazardous solvent or reagent be replaced with one that is less hazardous? Can a catalyst be used instead of a reagent? Is this reaction efficient or does it produce a significant amount of waste? How harmful is the waste? Again we refer to the twelve principles of green chemistry as we consider what to change and how.

Finally, green chemistry is always willing to take a “back to the drawing board” approach when a viable modification to an existing protocol cannot be found. This means completely reevaluating and developing entirely new processes when necessary.




Our Project:

The purpose of this project was to work with a chemistry teacher to develop a greener approach to one of the experiments in their curriculum – in this case it was the synthesis and analysis of aspirin.

Starting with a conventional protocol supplied by Ms. Daly at Bishop Guertin High School in Nashua, we developed three plans of approach to the greening of aspirin synthesis.




Our Plans:


PLAN A: Find Greener Solvent(s)

The protocol for synthesizing aspirin utilizes
acetic anhydride and either concentrated sulfuric acid or 85% phosphoric acid. As can be seen from the MSDS sheets, all of these chemicals have health and environmental risks associated with them. As such, all three of these are good candidates for replacement.

Ms. Daly does not plan to implement this lab with her class until the spring semester. She has instead suggested that the experiment be videotaped so that it can be shown to the class at the appropriate time.


Supply List:

· Salicylic acid
· Distilled water
· Ethanol
· Replacement for acetic anhydride
· Replacement for sulfuric or phosphoric acid


Risks and Safety Precautions:


Protective eyewear should be worn during this experiment as ethanol is a severe eye irritant. This experiment should be conducted in a well-ventilated area as ethanol is extremely flammable both as a liquid and as a vapor, and both ethanol and salicylic acid may cause irritation if inhaled. Gloves should be worn to avoid possible skin irritation.




PLAN B: Videotape the Existing Protocol


If we are unable to perform plan A due to the inability to find chemical substitutes, the standard protocol will be used and videotaped. A PowerPoint presentation will be developed and will include a series of questions along with it that the students will be asked to answer, as well as a discussion of green chemistry and atom economy. The video will be linked to our wiki site, allowing open access to students and teachers. The “green” principles addressed include the use of fewer energy inputs (no driving and no paper), and atom economy. It is our aim to influence others, through our presentation and discussion, to consider the twelve principles of green chemistry in their own chemistry protocols.



Risks and Safety Precautions

Since this plan calls for the use of acetic anhydride and phosphoric acid, it is extremely important that these chemicals be handled with caution, and that gloves, lab coat and eye protection be worn at all times. The reaction must be performed under the fume hood.





PLAN C: Develop a Case Study Based On the Boots Method of Ibuprophen Synthesis


If we are unable to perform either Plan A or Plan B, we will develop and post a presentation discussing the greening of the synthesis of ibuprophen.




What We Did:

After researching replacements for the hazardous chemicals used in the original protocol, we concluded that a viable alternative is not available to us at this time. As such, we moved on to Plan B and videotaped the standard experiment for educational purposes. The protocol for the synthesis of aspirin is outlined here. The changes to this protocol were made for the analysis of our aspirin product. We used a Mel-Temp apparatus rather than a LabPro to determine the melting point of the product. Also, Bishop Guertin's protocol tests the calorimetric absorbance of the sample to assess its relative purity. Our lab does not have this equipment. Instead, we performed a Thin Layer Chromatography analysis of our aspirin product. This protocol utilizes fewer solvents and smaller amounts of those that are used, making this portion of the experiment greener than the original.



The procedures were as follows:

Melting Point Determination

Protocol
1. Scoop a few of the dried crystals into a glass microcuvette. Turn it over and tamp lightly until the crystals are at the bottom.

2. Place the sample in the Mel-Temp apparatus equiped with a thermometer.

3. Slowly heat the sample to melting. One experimenter observes the sample to determine when it begins to melt, while the other experimenter observes the thermometer to record the temperature at which the sample melts.

4. Compare the observed melting point of the sample with the known melting point for aspirin (135 degrees Celcius).

Thin Layer Chromatography

Background
Thin layer chromatography (TLC) separates the components of a mixture between two phases. In this experiment a solid phase and a liquid phase were used. The solid phase, silica gel, slows down the progress of most components, so that they do not move as quickly as the liquid solvent phase. When different compounds are spotted together, they will travel at different rates along the solid phase due to differences in their attraction for the solid phase and differences in their solubility in the chosen solvent. Since the distance travelled by a substance in a given amount of time is a physical property of that substance, TLC can be used to assess the relative purity of a recrystallized product by cospotting the product with a pure sample and comparing their results. This experiment used TLC in this way; comparing a sample of the recrystallized product obtained from the synthesis portion with a laboratory-supplied sample of acetylsalicilic acid. If the product is relatively pure, it should spot similarly to the known sample of aspirin.

Supply List
Methanol
10:10:1 mixture of ethyl acetate, hexane, and glacial acetic acid

Protocol
1. Dissolve 1-2 g each of the known asprin and the recrytallized product separately in 5 ml of methanol in a small beaker.

2. Obtain a jar with a lid and add a piece of filter paper to act as a wick. Add approximately 10 ml of the developing solvent to the TLC chamber and return the top to the chamber.

3. Obtain a fluorescent TLC plate. Using a pencil, draw a line horizontally across the plate approximately 1 cm from the bottom.

4. Dip the end of a TLC spotter into each solution and spot the solutions separately just above the penciled line.

5. Place the TLC plate in the TLC chamber with the spotting end down. Do not allow the plate to touch the wick. Replace the top immediately.

6. Observe the solvent moving up through the solid phase. When it has almost reached the top, remove the plate from the chamber and immediately draw a line across the plate marking the top of the solvent front.

7. Allow the plate to dry completely. Place the plate under a UV lamp. Circle any visible spots with a pencil.














Discussion


The synthesis of aspirin is an acid-catalyzed esterification reaction in which a carboxyl group (-COOH) from acetic anhydride reacts with the phenolic alcohol group (-OH) attached to the salicylic acid This reaction forms a carboxylic ester – acetyl salicylic acid, or aspirin. The reaction can be written:


C7H6O3 + C4H6O3 ------> C9H8O4 + C2H4O2
Salicylic acid Acetic anhydride Acetyl salicylic acid Citric acid



From a green chemistry perspective, this reaction utilizes chemicals that are associated with health risks. There has been work on using solid acid catalyst (Bamoharramm et. al, 2007), which replaces the phosphoric acid and is more efficient than the liquid acid catalyzed method. The reaction can be carried out at room temperature, and the catalyst is recovered and reused, which would be considerably greener than our procedure. Unfortunately, the solid catalyst would have had to have been made in our lab. This is beyound the scope of this project, but would be an interesting and promising direction for future research.

For the current experiment, the efficiency of the reaction was calculated in terms of the “atom economy”. This is a green chemistry concept which is different from the traditional thinking about yield, which is a measurement of the amount of product obtained by a reaction as a proportion of the theoretical maximum that could be obtained from that reaction given the amounts of starting materials. It does not provide any information regarding how much waste is being generated by a reaction in the form of byproducts that are not part of the product. This is where atom economy comes in. Atom economy means looking at a reaction and tracking the fate of every atom; and then computing the amount of starting material that actually ends up in the product. This way of looking at reactions allows the experimenter to choose reactions that generate the least amount of waste possible.

Calculaing the atom economy for a particular reaction is fairly straightforward. First, the atomic masses of all the atoms used in the reaction are summed. Then, the masses of all the atoms used in the product are summed, as well as those wasted in the byproducts. The atom exonomy for the reaction is expressed as the percentage of the mass of the starting material that is in the product. For the synthesis of aspirin, the calculation is as follows:

Atomic mass of all atoms in starting material: 240.23g/mol

Atomic mass of all atoms used in the product: 180.17 g/mol

Atomic mass of all atoms wasted in the byproduct: 60.06 g/mol

Atom Economy (Theoretical): 180.17/240.23 x 100% = 75.00%

An atom economy of 75% indicates that three quarters of the starting materials ended up in the product. This calculation does not accound for the small amount of phosphoric acid that was used; but, neverthless, this reaction is reasonably green from an atom economy point of view. Also, the waste byproduct, citric acid, is a relatively non-hazardous substance.

In summary, this project looked at a popular high-school chemistry experiment from a green chemistry perspective. We concluded that while it would be ideal to find benign replacements for the solvents used in the synthesis of aspirin, this was beyond the scope of our project. Instead, we videotaped the original experiment and have posted it for educational purposes. We "greened" the analysis portion of the experiment using materials and equipment that we had in our lab. Finally, we calculated the atom economy for the synthesis reaction and found that the reaction fairly efficient and does not produce harmful waste.


Resources

Bamoharram FF, Heravi MM, Gharib A and Jahangir M. "Catalytic method for synthesis of aspirin by a green, efficient and recyclable solid acid catalyst (Pressler's anion) at room temperature". Journal of the Chinese Chemical Society, 2007, 54,1017-1020.

Bishop Guertin website Bishop Guertin

Doxee KM and Hutchinson JE."Green Organic Chemistry: Strategies, Tools and Laboratory Experiments". Thomson Brooks/Cole, 2004.

EPA website
http://www.epa.gov/