Abstract Acetylsalicylic acid (commonly known as ‘aspirin’) was synthesized (1. 11 g, 34. 05% yield) from salicylic acid and acetic anhydride. The final product was a white crystalline solid and an unknown amorphous substance that was beige in color. The melting range was 132. 5-136°C as compared to 138-140°C for an authentic sample of acetylsalicylic acid. The infrared spectrum for the experimental sample shared nine major absorptions in the spectrum (2200-600 cm-1 range) with those from the spectrum of the authentic sample.
The level of agreement between the data was considered to be sufficient to identify the final product as acetylsalicylic acid. Several molecular vibrations were investigated using molecular modeling to predict the positions of their absorptions in the infrared spectrum. The percent yield was low, suggesting that some acetic anhydride may have failed to react with salicylic acid. However, the melting range of the synthesized acetylsalicylic acid was close to the melting range of an authentic sample. Introduction.
Aspirin or acetylsalicylic acid, is a derivative of salicylic acid that is a mild, nonnarcotic analgesic useful in the relief of headache and muscle and joint aches. The drug works by inhibiting the production of prostaglandins, body chemicals that are necessary for blood clotting and which also sensitize nerve endings to pain. The father of modern medicine was Hippocrates, who lived sometime between 460 B. C and 377 B. C. Hippocrates was left historical records of pain relief treatments, including the use of powder made from the bark and leaves of the willow tree to help heal headaches, pains and fevers.
By 1829, scientists discovered that it was the compound called salicin in willow plants which gave you the pain relief. According to “From A Miracle Drug” written by Sophie Jourdier for the Royal Society of Chemistry: “It was not long before the active ingredient in willow bark was isolated; in 1828, Johann Buchner, professor of pharmacy at the University of Munich, isolated a tiny amount of bitter tasting yellow, needle-like crystals, which he called salicin. Two Italians, Brugnatelli and Fontana, had in fact already obtained salicin in 1826, but in a highly impure form.
By 1829, Henri Lerouxhad improved the extraction procedure to obtain about 30g from 1. 5kg of bark. In 1838, Raffaele Piria (an Italian chemist) then working at the Sorbonne in Paris, split salicin into a sugar and an aromatic component (salicylaldehyde) and converted the latter, by hydrolysis and oxidation, to an acid of crystallised colourless needles, which he named salicylic acid. Henri Leroux had extracted salicin, in crystalline form for the first time, and Raffaele Piria succeeded in obtaining the salicylic acid in its pure state.
The problem was that salicylic acid was tough on stomachs and a means of ‘buffering’ the compound was searched for. The first person to do so was a French chemist named Charles Frederic Gerhardt. In 1853, Gerhardt neutralized salicylic acid by buffering it with sodium salicylate and acetyl chloride, creating acetylsalicylic acid. Gerhardt’s product worked but he had no desire to market it and abandoned his discovery. In 1899, a German chemist named Felix Hoffmann, who worked for a German company called Bayer, rediscovered Gerhardt’s formula.
Felix Hoffmann made some of the formula and gave it to his father who was suffering from the pain of arthritis. With good results, Felix Hoffmann then convinced Bayer to market the new drug. Aspirin was patented on February 27, 1900. The scientists at Bayer came up with the name Aspirin. It comes from the ‘A” in acetyl chloride, the “spir” in spiraea ulmaria (the plant they derived the salicylic acid from) and the ‘in’ was a then familiar name ending for medicines. In 1915, the first Aspirin tablets were made. 1 Many other derivatives of salicylic acid have been tried, but none work as effectively as aspirin.
Aspirin may cause side effects such as stomach irritation, thinning of the blood, and possible allergic reactions. In addition to analgesic properties, aspirin is also an antipyretic (fever reducer) and an antirheumatic (used in treating arthritis). Side effects of aspirin, besides stomach irritation, include thinning of the blood and possible allergic reactions. Many commercial suppliers of aspirin use additives such as sodium bicarbonate, sodium citrate, aluminum hydroxide and others to counteract the acidity of aspirin. In general, all brands of aspirin work about equally well.
In recent years other analgesics, acetaminophen and ibuprofen, have gained widespread over the counter use. Acetaminophen, found in Tylenol and Datril, has both analgesic and antipyretic activity. Acetaminophen does not reduce swelling but is the only analgesic of these three which is recognized as safe for use during pregnancy. Ibuprofen, the active ingredient in Motrin, Advil and Nuprin, is not only a pain reliever, but is also an excellent anti-inflammatory agent and is comparable to aspirin in the treatment of arthritis.
The anti-inflammatory activity is attributed to the fact that these agents inhibit prostaglandin synthesis in the body. Several products, such as B. C. powders and Goody’s headache powder, are available which contain a combination of more than one type of analgesic. The chemical structures of acetaminophen, ibuprofen, as well as the synthesis equation for aspirin, are shown below. In the synthesis of aspirin, salicylic acid behaves as an alcohol and reacts with acetic anhydride (with a small amount of sulfuric acid acting as a catalyst) to produce an ester (alcohol and carboxylic acid).
Each molecule of acetic anhydride forms two molecules of acetic acid in its reaction with water. The acetic acid couples with the –OH group on the salicylic acid molecule in a dehydration reaction to produce Aspirin and water. The water produced reacts further with the acetic anhydride to perpetuate the reaction. Aspirin has a low solubility in cold water, so excess reactants can be washed away with cold water, which leaves the Aspirin free of any excess acid. The melting point, the temperature at which the solid state of a substance is transformed into the liquid state, is a property of many substances.
The melting point as determined on a sample is actually a range of temperatures, from the temperature at which the sample first begins to melt to the temperature at which the final amount of solid disappears. Two types of information can be obtained from these ranges: the location of the range on the temperature scale for a pure sample when compared with a list of known melting points can be used to help identify the substance, and the purity of the sample as indicated by the breadth of the range. A narrow (2 degrees or less) range indicates a pure sample and the broader the range, the lower the purity.
Impurities not only broaden the range for a substance, but they also cause the range to be depressed below the range for the pure substance. Infrared spectroscopy is used to identify functional groups and types of bonds within molecules. Infrared radiation is absorbed by molecular vibrations that result from the stretching and bending of bonds within the molecule. 2 Certain bond types between certain atoms absorb this radiation at certain values. The spectrum of absorbed infrared radiation is usually displayed on the wavenumber (cm-1) scale.
Each molecule displays a characteristic infrared absorption spectrum which can be compared to those stored in an electronic library for identification of a compound because it has a unique set of atoms and bond types. Molecular modeling is a computer-based technique for constructing molecular structures. With the aid of quantum mechanical methods such as molecular orbital calculations, molecular modeling can display the fundamental modes of vibrations within molecular structures and predict the positions of absorption for these modes in the infrared spectrum.
Experimental Procedure Pure salicylic acid (2.5309 g) was weighed into a 150 mL Erlenmeyer flask and 8 mL of acetic anhydride were carefully added under a fume hood. The flask was then placed in boiling water and 10 drops of 85% H3PO4 were added to the flask.
The mixture was stirred until the solid had completely dissolved. While the flask was being heated, a beaker containing 100 mL of distilled water was placed in an ice bath. After 15 minutes of heating the flask, the flask was removed and placed on the bench top to allow cooling. Slowly, 10 drops of the cold distilled water was added to the flask. An additional 15 mL of cold distilled water was added to the Erlenmeyer flask.
The flask was placed in the ice bath. Since crystallization did not occur after 5 minutes, the inside of the flask was gently scratched using a stirring rod. When the mixture gained a slushy consistency, the flask was removed from the ice bath. A vacuum filtration apparatus was setup under a hood. The aspirin crystals were filtered. Small amounts of cold water was used to rinse out any remaining crystals in the flask. The solid air-dried for several minutes through the filtration device. The aspirin crystals were placed in 20 mL of distilled water. While stirring, the solution was heated in a water bath until all the crystals dissolved.
After the crystals had dissolved, the flask was removed from the water bath and placed on the bench top for 5 minutes to cool. After the re-crystallization was complete, the flask was placed in an ice bath for 5 minutes. The aspirin crystals were then purified again using the filtration apparatus and was washed with 5 mL of cold distilled water. Acetylsalicylic acid (1. 11 g, 34. 05% yield, 132. 5-136°C melting point) was obtained. The melting points of authentic samples of salicylic acid and acetylsalicylic acid were determined simultaneously with that of the synthesized sample of acetylsalicylic acid.
Melting points were determined in capillary tubes using a MelTemp apparatus. The infrared spectrum of the synthesized acetylsalicylic acid was obtained using the total internal reflectance technique on a Thermo Fourier Transform IR Spectrometer. Authentic infrared spectra of acetic anhydride, acetylsalicylic acid, and salicylic acid were provided for comparison. Molecular modeling of some fundamental vibrational modes for acetylsalicylic acid was illustrated using the Spartan Plus software. Data and Results Mass of acetylsalicylic acid – 1. 11g Table 1. Melting Point Data.
Compound| Start Melting °C Finishing Melting °C Range Mid-Point °C| Salicylic acid| 158 164 161| Acetylsalicylic acid (authentic)| 137 141 139| Acetylsalicylic acid| 132. 5 136 134. 25| Table 2. Results of Molecular Modeling on Acetylsalicylic acid Type of stretch| Frequency (cm-1)| O-H | 3884. 28| C-O| 2005. 52| C=O| 1932. 93| C-C| 1780. 83| C-H| 3407. 30|
Calculations Theoretical yield of acetylsalicylic acid = 3. 26g % yield of acetylsalicylic acid = (actual yield(g)/theoretical yield(g)) x 100 = (1. 11g/3. 26g) x 100 = 34. 05% g of salicylic acid = 2. 53g (Limiting reagent)g of acetic anhydride = 8. 64g Data and Conclusion The synthesis of acetylsalicylic acid from salicylic acid was successfully accomplished.
The percent yield, 34. 05%, is a low percent yield. Many reactions do not reach equilibrium at a position in which not all of the starting material is converted to product. Since acetylsalicylic acid was recrystallized from water, some of the product was left in the filter. An observation was made that crystals were left behind on the filter paper in the filtration apparatus and on the inside of the flasks when the crystals were transferred from the flask.
Perhaps an extra rinse or two of distilled water would have washed the crystals out. The extra water would have been filtered from the solid product. Also, a small amount of a beige, amorphous substance was left behind after the final product had dried. This was most likely unreacted salicylic acid. The weight of the unreacted reagent certainly causes the percent yield to be so low. The flask could have been left in the ice bath a little longer to ensure complete crystallization. Melting point analysis suggests that the white, crystalline product was in fact acetylsalicylic acid.
The known melting range for authentic acetylsalicylic acid, 137-141°C, was close to the melting range for the synthesized acetylsalicylic acid, 132. 5-136°C. The material isolated was not acetic anhydride, since it is a liquid at room temperature. The material also could not have been salicylic acid, as its melting range, 158-164°C is far removed from the melting range for the synthesized acetylsalicylic acid. The infrared spectroscopic analysis of the product confirms its identity as acetylsalicylic acid. Nine major peaks from each spectrum match up very well. See Figures 1 & 2.
There is no comparable degree of agreement between the peaks listed for the product and those listed for acetic anhydride or salicylic acid. The reason for these differences in the intensities of some peaks is attributed to the fact that the experimental sample was run using the total internal reflectance technique, whereas the other spectra were taken from known spectra and probably run using a different technique. Molecular modeling was used to illustrate different fundamental modes of vibration for the acetylsalicylic acid molecule and to obtain the values for the positions where these modes would absorb infrared energy.
The only vibration with a value within the range of the limits for the experimental spectra was C-C. The C-C bond had a value of 1780. 83 cm-1. No comparison between the values can be made. The cm-1 values are related to the frequencies of the vibrations. Bonds between atoms can be considered to be like springs which can vibrate by stretching and bending. One can see that when hydrogen is bonded to an atom, the bond is like a tight spring which would have a high frequency of vibration. The other values with heavier atoms and longer bonds would vibrate like longer springs with a lower frequency of vibrations.
Molecular modeling is a very approximate technique which relies on theoretical methods that involve a large number of assumptions to simplify the calculations which lead to the results. An exact correlation isn’t expected. This experiment in which acetylsalicylic acid was synthesized from salicylic acid proved to be mainly successful. As described earlier, some different methods could have been adopted to ensure that all of the salicylic acid reacted.
References (1) Jeffreys, Diarmuid Aspirin: The Remarkable Story of a Wonder Drug, Bloomsbury Publishing USA, 2005 (2) Conley, Robert T. Infrared spectroscopy. Allyn and Bacon, 1972.