Synthesis of Aspirin A General Chemistry Experiment, Lecture notes of Chemistry

Download Synthesis of Aspirin A General Chemistry Experiment and more Lecture notes Chemistry in PDF only on Docsity! In the Laboratory JChemEd.chem.wisc.edu • Vol. 75 No. 10 October 1998 • Journal of Chemical Education 1261 In recent years, examples from organic chemistry have come to play increasingly prominent roles in the first-year university general chemistry course. The American Chemical Society has recommended more integration of biological concepts into college-level introductory general chemistry courses. Following this recommendation, at least two current general chemistry textbooks make liberal use of organic examples (1), and some universities are bringing organic chemistry much more into the forefront of the introductory course (2). At California State University, Fullerton, the first-semester general chemistry laboratory has been redesigned over the past several years. The redesign has added an organic component and provided students with explicit examples of several types of operations in which chemists engage: observation, synthesis, quantitative measurements, construction of apparatus, and chemical analysis. Our experiment that accentuates accurate quantitative measurements was reported earlier (3). Over the course of the first semester and the beginning of the second, our general chemistry students synthesize two organic substances (aspirin and methyl orange) and two inorganic substances (alum and potassium ferrioxalate). An earlier paper described our ferrioxalate synthesis experiment (4). This paper describes the first of our organic synthesis experiments, the synthesis, purification, and qualitative spec- troscopic characterization of aspirin. Aspirin (acetylsalicylic acid) is a pain-relieving compound familiar to virtually all students. The synthesis of aspirin from oil of wintergreen is an example of one of the most prevalent, profitable, and honored activities of chemists: the conversion of a naturally occurring substance into one with therapeutic value. Simple enough to be accomplished and understood by beginning students, this synthesis nevertheless serves as a paradigm for the pharmaceutical industry, from tranquilizers and antibiotics to yet-undiscovered agents for treating cancer, heart disease, and AIDS. Rationale The two-step conversion of oil of wintergreen (methyl 2- hydroxybenzoate) into salicylic acid (5) and then into aspirin (6 ) serves as an introductory example of multistep sequen- tial synthesis. It also provides practice in molecular pattern Synthesis of Aspirin A General Chemistry Experiment John Olmsted III Department of Chemistry and Biochemistry, California State University, Fullerton, Fullerton, CA 92834 C C C H C C C CH HH O O O R1 R2 Reactive sites Common Core Compound Oil of Wintergreen Salicylic Acid Aspirin R1 CH3 CH3 H H R2 H H C O Figure 1. The structural core common to oil of wintergreen, salicylic acid, and aspirin. OH– C C C H C C C CH HH O O O CH3 H C C C H C C C CH HH O– O O CH3 C C C H C C C CH HH O– O– O C C C H C C C CH HH O– O– O + H2O+ 2 H2O+ 2 H3O ++ C C C H C C C CH HH O– O O CH3 OH–+ I. Deprotonation of oil of wintergreen II. Attack by hydroxide anion O– O– CH3 C C C H C C C CH HH O O H O– O– CH3 C C C H C C C CH HH O O H CH3OH–+ III. Elimination of methanol C C C H C C C CH HH O O O IV. Protonation of dianion H H Figure 2. Reaction mechanism for the conversion of oil of winter- green into salicylic acid. recognition, as the reactions modify the periphery of a struc- tural core common to the starting material, intermediate product, and final product (Fig. 1). Viewed from another perspective, this sequence exem- plifies two of the most common types of chemical reaction, hydrolysis and condensation: HOC6H4CO2CH3 + H2O → HOC6H4CO2H + CH3OH Hydrolysis HOC6H4CO2H + (CH3CO)2O → CH3CO2C6H4CO2H + CH3CO2H Condensation As illustrated in Figure 2, the hydrolysis reaction pro- ceeds in several steps involving deprotonation and protona- tion as well as cleavage of a C–O bond (7 ). These encom- pass examples of Brønsted acid–base proton transfer, another major class of chemical reactions. These structural changes manifest themselves through readily observed macroscopic changes as the synthesis pro- ceeds. Addition of aqueous base to syrupy, fragrant oil of wintergreen yields a white odorless solid. Upon heating, this In the Laboratory 1262 Journal of Chemical Education • Vol. 75 No. 10 October 1998 • JChemEd.chem.wisc.edu solid reacts further to yield a solution, from which a different white solid precipitates upon acidification. On heating with acrid liquid acetic anhydride, salicylic acid reacts and dissolves. Dilution with water and cooling results in precipitation of aspirin, yet another white solid. Synthesis must always be accompanied by isolation and purification of the product. Both salicylic acid and aspirin are sparingly soluble in water, making these procedures readily accessible to the general chemistry student. Isolation is easily accomplished by suction filtration using a Büchner funnel apparatus, and purification is equally easily accomplished by dissolving the crude product in hot water and chilling to recrystallize the pure product. A newly synthesized chemical substance must be appro- priately characterized before the synthesis can be judged a success. While characterization is multifaceted and typically involves techniques well beyond the scope of general chemistry, FTIR spectrophotometry is well suited to characterization of aspirin and its precursors. By taking FTIR spectra of their products, our students not only “see” that their white solids are distinctly different but also become familiar with one of the most prevalent instruments of the contemporary laboratory. Figure 3 shows actual FTIR spectra taken under the same conditions that are used by our students. The three compounds share spectral features due to their common framework, for example the aromatic C–H bending vibrations in the 600– 800 cm{1 region. They differ substantially in the absorptions arising from the CO2H, CO2, and OH groups. Aspirin lacks the broad hydrogen-bonded OH absorption that is promi- nent in oil of wintergreen and salicylic acid between 3000 and 3500 cm{1. On the other hand, whereas oil of winter- green and salicylic acid have a single C=O absorption at about 1700 cm{1, aspirin has two distinct peaks arising from its ester and acid C=O groups. Procedure Outlined here is a compact version of the procedure carried out by our students and the instructions for their laboratory report. The procedure given to the students includes more detailed specifications for standard techniques with which they may not be sufficiently familiar. Pan balances provide sufficient accuracy for all weighings, and graduated cylinders provide sufficient accuracy for volume measurements. Glassware can be cleaned by rinsing with deionized water and need not be dry except when explicitly noted. Isolation of solids is accomplished by cold suction filtration using a Büchner funnel. The filtrate from the first synthesis procedure is substan- tially acidic and should be disposed of properly following procedures for acidic aqueous waste. All other liquid waste is relatively benign and can be rinsed down the sink. Conversion of Oil of Wintergreen to Salicylic Acid Transfer 4 ± 0.2 mL of oil of wintergreen to a previously weighed clean, dry 250-mL beaker and reweigh. Add, with stirring, 40 mL of 6 M NaOH (precipitate forms). Heat with occasional stirring to a gentle boil, reduce the heating rate to avoid “bumping”, and continue boiling gently for 15 min- utes. Midway through heating, rinse any solids adhering to the beaker walls into the solution with a small quantity of deionized water. Cool the beaker in an ice bath until it is just warm to the touch. Without removing the beaker, slowly add, with continuous stirring, 50 mL of 8 M H2SO4 (precipitate forms). After chilling in the ice bath, isolate the product. Rinse the beaker with iced deionized water, pour over the precipitate, and continue suction for about 10 minutes. Transfer the crude solid to a 250-mL beaker containing 100 mL of deionized water. Heat to a gentle boil until the solid dissolves completely. Allow the beaker to cool (crystals form), then transfer the beaker to an ice bath and chill thor- oughly. Isolate the product. Rinse the beaker with 50 mL of iced deionized water, pour over the precipitate, and continue suction for 15 minutes. Spread the solid on a watch glass, cover with filter paper, and store overnight until dry. Conversion of Salicylic Acid into Aspirin Weigh 1.4 g of salicylic acid and transfer to a clean, dry 125-mL Erlenmeyer flask. Add 3.0 mL of acetic anhydride (CAUTION: caustic vapors: use a hood) and 5 drops of con- centrated H3PO4. Stopper with a one-hole rubber stopper fitted with 2 cm of plastic tubing. Float the Erlenmeyer flask in an 800-mL beaker containing 250 mL of water. Heat this beaker to 85 °C and maintain between 85 and 90 °C for five minutes (CAUTION: do not boil; steam baths may be used if available). Discontinue heating and immediately use a Pasteur pipet to deliver 2 mL of deionized water through the plastic tubing (CAUTION: hot acid vapors). When the flask is suffi- ciently cool, remove it using a towel, remove the stopper, and add 20 mL of deionized water. Allow to stand at room temperature until crystals begin to form. Then add 10 mL of deionized water, swirl, and place the flask in an ice bath. After chilling, isolate the product. Rinse the flask with 15 mL of iced deionized water, pour over the precipitate, and continue suction for about 10 minutes. Weigh the solid in a clean, dry 50-mL beaker and add to the beaker 10 mL of deionized water per gram of solid. Heat with continuous stirring until all solid dissolves. Transfer the beaker to an ice bath and chill (crystals form) until precipi- tation appears complete. Isolate the product and continue suction for an additional 10 minutes. Then transfer the solid to a clean, dry 50-mL beaker and oven-dry at 80 °C (CAUTION: aspirin melts and decomposes at 100 °C) for one hour. Remove, cool, and weigh the final product. Figure 3. FTIR spectra of oil of wintergreen, salicylic acid, and aspirin.