Esterification: The Synthesis of Aspirin (ASA) Introduction Most of us are familiar with esters, but are not aware

of their presence in our everyday life. Methyl salicylate, for example, is oil of wintergreen, isopentenyl acetate is oil of banana or pear, butyl butanoate smells like pineapple, propyl-2-methylpropanoate smells like rum and pdimethylterephthalate and ethylene glycol (antifreeze) are used to make Dacron. Medicinally, the most common ester is aspirin (ASA; acetyl salicylic acid). Other drugs such as Worm Guard (anti-wormer), Maxicaine (local anesthetic), Malathion (organophosphate), Mebendazole (antihelmenthic), Demerol (narcotic analgesic) and Equinil (sedative) are also esters. Theory Esterification is simply the reaction between a carboxylic acid and an alcohol which is catalyzed, in this case, by a mineral acid, e.g., sulfuric or phosphoric acids. In general, the mechanism for esterification follows the following scheme (illustrated, above and below, as well): The proton from the acid attacks the carboxyl oxygen which in turn "pushes" the two electrons in one of the bonds "down", i.e., it delocalizes the electrons and "spreads them out" between the two oxygen atoms. The delocalized electrons then, in the presence of the alcohol, rearrange in such a manner as to create a temporary bond between the two reactants. Note that the alcoholic oxygen atom has a temporary positive charge to it in the intermediate in step #2. The proton (Step #3) from the alcohol attacks the oxygen in the original -OH portion of the acid forming a positively charged oxygen atom and a sort of water molecule still attached to the intermediate. The electrons "holding" the "water" to the intermediate "flip down", releasing this water, leaving the delocalized intermediate in the end of Step 3. In Step #4, the proton added in Step 1 leaves and the electrons left behind flip down "closing" the double bond on the oxygen atom and leaving the ester product. The starting reactants for this experiment are salicylic acid and acetic anhydride, image left.

Salicylic acid reacts better with acetic anhydride (what is an anhydride?) than acetic acid, so acetic acid will provide the acetyl group which will react with the alcoholic -OH group on the salicylic acid as follows, image right: Note that this mechanism follows the general reaction mechanism previously discussed. Materials and Methods Chemicals Salicylic acid Acetic anhydride Concentrated sulfuric acid Electronic pan balance and weighing boat Equipment/Supplies 250 mL Erlenmeyer flask Hot water bath Ice bath Buchner funnel and filter paper Glass stirring rod Put 3 grams of salicylic acid and 6 mL of acetic anhydride in a 250 mL Erlenmeyer flask. Add 4 drops of concentrated sulfuric acid to the mixture and stir. Although this reaction has been micro-scaled, it is possible that you may feel the reaction vessel becoming warm. If you do not feel it getting warm, add another 2 drops of the con sulfuric acid to the reaction mixture and place the reaction vessel in the hot water bath (50 C) for 10 minutes. This step will allow the reaction to run to completion. Next, cool the flask in an ice bath and add 50 mL iced water slowly. Stir until precipitation is complete, then filter over a Buchner funnel and rinse the crystals several times with ice water. Place your samples in the incubator to dry. Questions Complete the Questions on separate paper and attach to this experiment for turn-in. 1. Would you feel comfortable taking the ASA you made in this lab? Why or why not? 2. What technique would you do to feel safe in taking the ASA you made in the lab? 3. What purpose does the acid in this experiment serve? 4. Library assignment: find the structures of acetaminophen, ibuprofen and ASA. Draw them out. Do these compounds have similarities? Differences? What are they? 5. Write out the complete reaction mechanism (to include intermediates and structures) for the reaction of trans-cinnamic acid with ethanol to form ethyl cinnamate (one part of the sex pheromone of the male oriental fruit moth). 6. Write out the complete reaction mechanism (to include intermediates and structures) for the reaction of 1-methyl-4-phenyl-4piperidinecarboxylic acid with ethanol to form Demerol. The structure of 1-methyl-4-phenyl-4-piperidinecarboxylic acid is as follows, slight upper right: This page reconstructed 11 August 2008, 1533 hours, PDT.