Question

PREPARATION OF PHARMACEUTICALS - Fischer Esterification Reactions

Q: Calculate the expected mass of both methyl salicylate and aspirin assuming 100% yield.

EXPERIMENT7 PREPARATION OF PHARMACEUTICALS Fischer Esterification Reactions Almost 2500 years ago, physicians such as Hippocrates recommended that patients chew on the bark of the willow to alleviate pain. The active ingredient in willow bark was found to be salicin, a compound made of a molecule of salicyl alcohol bonded to a p-D-glucose molecule. In the stomach, the bond between salicyl alcohol and the glucose molecule was hydrolysed, and then the salicyl alcohol was oxidised to salicylic acid CH2OH CH2OH OH Ogcose CH OH Salicin (found in willow bark) Salicylic acid 2-hydroxybenzoic acid Salicyl alcohol Plain salicylic acid was found to be an even more effective pain reliever than willow bark, and without the bitter taste and need for a willow tree in the front yard Unfortunately, one of the side effects of using salicylic acid is the severe irritation of the mucous lining of the stomach because of the acidity of the molecule. Ester derivatives of salicylic acid have similar pharmaceutical benefits, but without the side effects Salicylic acid is a di-functional compound as it contains both a carboxylic acid (CooH) and an alcohol (OH) functional group. Esters of salicylic acid may be formed if the acid group reacts with an alcohol or if the alcohol group reacts with an acid. In this experiment, we use both of these possible reactions to make two pharmaceutical products, each containing an ester functional group 50 METHYL SALICYLATE Methyl salicylate (oil of wintergreen) is made by the reaction of methanol with the carboxylic acid group present in salicylic acid. It is used extensively in rubbing liniments, perfumes and as a flavouring agent. You will recognise the odour methyl salicylate as similar to that of 'Dencorub' or other heat creams OH +CH3OH H2SO4 OCH3 +H20 CH Salicylic acid MW 138 Methyl salicylate (oil of wintergreen) MW 152 ASPIRIN o-acetylsalicylic acid (aspirin) is made by the reaction of the phenol group of salicylic acid with acetic anhydride. Aspirin is said to be the most widely used drug in the world. As with most salicylates, aspirin lowers the body temperature rapidly and effectively in subjects with fever and is also a mild analgesic. Commercial aspirin tablets contain about 325 mg of aspirin held together by an inert binder such as starch, clay or sugar. The mild stomach irritation experienced by some people taking aspirin is the result of the acidic nature of this compound H2504 он OH + CH3COOH Acetic acid CH3 Salicylic acid MW 138 Acetic anhydride H3C o-acetylsalicylic acid (aspirin) MW- 180 51 - SCHEDULE Activity Lab start time Safety brief given by lecturer Part 1 reflux set up, checked by staff, heating Part 2 aspirin mixture heating on bath Part 2 aspirin recrystallisation in progress Part 1 reflux complete, sufficiently cooled, started isolation Both samples finished, going into sample containers Commence clean up Time 0:15 0:15 0:30 0:15 0:15 0:55 0:15 PRE-LAB TASKS Methyl salicylate 1. Calculate the expected mass of methyl salicylate, assuming 100% yield 2. Construct a flow chart for methyl salicylate part of the experiment 3. Predict and explain the result you would expect when conducting a phenol test with methyl salicylate Aspirin 4. Calculate the expected mass of aspirin, assuming 100% yield 5. Construct a flow chart for the aspirin part of the experiment 6. Write the equation for the reaction of acetic anhydride with water. Why is it so important to keep the reaction flask dry during the synthesis of aspirin? Both products 7. Do an analysis of the IR and NMR spectra of the two different products you will be making from salicylic acid. (Spectra on Blackboard) 52- PROCEDURE PART 1: METHYL SALICYLATE CAUTION: Concentrated sulfuric acid is corrosive. Phenol is corrosive. DCM irritating to airways. Acetic anhydride is corrosive Use in the fumehood where possible. Handle with care! Preparation Dissolve salicylic acid (4.0 g) in methanol (25 mL) in a 50 mL dry round-bottom flask. In the fumehood, gradually add concentrated sulfuric acid (5 mL) to the flask with gently swirling. Add a boiling chip. Secure the flask with a clamp and assemble the reflux apparatus (Figure 3) Gently reflux the mixture for 90 minutes, ensuring the water flow through the condenser is steadv but not excessive While the mixture is refluxing, complete the procedure for the preparation of aspiin. it is essential that you get back to this reaction with 30-40 minutes of working time left, so do not let yourself get caught up with the aspirin preparation Isofation At the end of the reflux time, remove the heating mantle and allow the flask to cool for a few minutes until it can be handled safely Tip the contents of the flask (not boiling chips, if possible!) into a large separating funnel containing cold water (50 mL) and dichloromethane (10 mL). Shake gently and release the vapours Separate the two layers, keeping the organic layer Place the aqueous layer back into the separating funnel and extract again with dichloromethane (10 mL). Separate layers and combine the organic layers Return the combined organic layers to the separating funnel and wash with NaHCO3 solution (10%, 10 mL) to remove any acid residue remaining in the organic layers. Separate and retain the organic layer in a dry beaker or flask Add a small amount of drying agent (anhydrous calcium chloride or sodium sulfate) and swirl. If the organic layer is still cloudy, add a little more, then stopper and let stand for 5 minutes. Decant the liquid from the flask into another dry small conical flask, add one boiling chip, then evaporate the dichloromethane using the cooler' water bath (70 °C) in the fumehood The methyl salicylate product should be a clear or pale yellow oily substance. Place the oil into a pre-weighed glass sample tube, calculate the percentage yield and hand the labelled sample to the demonstrator Percentage yield Mass of product obtained x 100 Mass of product expected Purification In an ideal situation, the crude methyl salicylate would then be distilled and the fraction that boils at the BP of methyl salicylate would be collected. Given the size of your sample, you might appreciate why this step is omitted. Ensure all glassware is washed with warm, soapy water and scrubbing brushes before being returned. PROCEDURE PART 2: ASPIRIN CAUTION: Concentrated sulfuric acid is corrosive Use in the fumehood where possible. Handle with care! Preparation Place salicylic acid (4.0 g) in a dry 250mL conical flask. In the fumehood, add acetic anhydride (10 mL), followed by concentrated sulfuric acid (10 drops) and swirl the flask gently until most of the salicylic acid dissolves. It is very important that only dry glassware and plastic droppers are used. Any water in the mixture will prevent the esterification reaction from occurring to any great extent. Heat the flask on the hottest water bath (90 °C) in the fumehood for 10 minutes. Remove flask from the water bath and, while still hot, cautiously add water (4 mL) in one portion. (CAUTIONI The solution may boil from the heat of decomposition of the excess acetic anhydride). You may now remove your flask from the fumehood 54 solation Add water (100 mL) and stir the solution until white solid starts to form. Cool the mixture in an ice-bath to complete the crystallisation. If your mixture appears to have an oily material but no crystals, consult your demonstrator. You may still have time to repeat the preparation step Collect the product crystals by vacuum filtration using a Buchner funnel. Wash the product twice with ice-cold water (10 mL each wash) Phenol test (check with tutor whether this is required) At this point, it is useful to carry out a phenol test, to determine if there is any salicylic acid impurities in the crude product. Put water (5 mL) into three clean test tubes. Dissolve a few crystals of phenol (first test tube), salicylic acid starting material (second test tube) and the crude product (third test tube). Do not contaminate samples - clean your spatula! Add dilute FeCl3 solution (5 drops) to each test tube and shake well. The formation of colour ranging from a red to a violet indicates the presence ofa phenol functional group, the actual colour depending on the particular phenol. Note that FeCls solution is orange-yellow. Record all results Purification (by recrystallisation) A mixture of ethanol and water will dissolve impurities such as salicylic acid, but the product aspirin will be insoluble at low temperatures. Allow 15-20 minutes to complete this section Weigh the crude aspirin and calculate the volume of ethanol required to dissolve it (10 mL of ethanol will dissolve 6 g of aspirin). Heat the ethanol on the 'cooler water bath 70 °C) almost to boiling point and dissolve the crude aspirin Warm some distilled water (10 mL per 6 g of aspirin) and add to the ethanol mixture when the aspirin has dissolved. If crystals form at this stage, heat the mixture again on a water bath until they re-dissolve. Let the ethanol-water solutiorn cool slowly with the mouth of the flask covered to prevent evaporation of the ethanol. When the solution has cooled to room temperature, cool further using an ice bath Collect the product by vacuum filtration using a Buchner funnel, wash with a little ice-cold distilled water and air dry Test the purified product with FeCla solution as before. Ideally, there should be no indication of phenol functional groups because any excess salicylic acid has been removed Weigh the product and calculate the percentage yield. Place sample into a plastic sample container with appropriate label. This is the sample of aspirin you will use for the chromatography experiment next week. Percentage yieldMass of product obtained x 100 Mass of product expected Ensure all glassware is washed with warm, soapy water and scrubbing brushes before being returned DISCUSSION Justify the yield you have obtained for each product POST-LAB QUESTIONS 1. Draw the reaction mechanism for the esterification of salicylic acid with methanol to form methyl salicylate (Hint: The general name for this type of reaction is Fischer esterification. Be specific do not draw a general mechanism with "R" groups.) 2. What is the purpose of the concentrated sulfuric acid used in the preparation of aspirin? 56 3. Copy and complete the following table by writing 'soluble' or 'insoluble' in the appropriate spaces. For each soluble combination, draw the structure of the organic molecule as it exists in the solution. An example has been done for you. Water 10% NaHCO3 solution (a weak base) 10% NaOH solution (a strong base) Sacylc acid Methyl salicylate Soluble Aspirin - 57

Answer 1

刁M as aspirin он as au 3 Moim Soluble soluble so クへ。 oH Soluble Aolubla