Objectives

Many kind of naturally emerging chemicals can be offered isolated and also supplied to make various other compounds. Methyl salicylate is a normally arising compound that we will certainly usage to produce salicylic acid, which will then be offered to make the wonder drug aspirin (acetylsalicylic acid). This is not the source of salicylic acid in the industrial synthesis of aspirin, yet it is, nevertheless, a great one for laboratory use. Two different chemical approaches will certainly be employed. First is hydrolysis, which is the breaking of a bond via water. Esters are quite conveniently hydrolyzed into their two beginning components, an acid and also an alcohol. Then, we percreate an ester synthesis for the formation of aspirin. Equilibrium favors hydrolysis, however utilizing acetic anhydride as the acid resource avoids this backward reaction, because water is not created throughout ester formation. Both salicylic acid and aspirin are quickly isolated.

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Background

Methyl salicylate (an ester) deserve to be hydrolyzed to produce salicylic acid. The 2 different functional groups on the aromatic ring are utilized in this lab. First, the totally free carboxylic acid team will certainly be developed as soon as we hydrolyze the methyl salicylate. Methanol is the alcohol which is released by hydrolysis. 2nd, the hydroxyl team on salicylic acid will be provided in ester formation to develop aspirin. When we perdeveloped an ester synthesis formerly, we took one-of-a-kind prewarns to prevent water from being produced (we included a dessicant in the reactivity mixture and also had a drying tube afresolved on height of the reflux column). Acetic anhydride will be used in this experiment so that as soon as ester is developed, water is not produced. As a result, the thermodynamic equilibrium will certainly currently be for the development of an ester rather of its hydrolysis. Before proceeding with the experiment you must review numerous items. First, you have to be acquainted with the ester functional group. Esters are developed when an acid and an alcohol integrate. You need to be able to conveniently recognize an ester by looking at the structural formula. There are just 3 kinds of compounds which have an oxygen situated in between 2 carbons. These are ethers, esters and also acid anhydrides. Can you identify the differences? Second, we will perdevelop a hydrolysis reactivity. Hydrolysis occurs once water is used to break a bond. Hydrolysis have the right to occur in either basic or acidic problems. We will certainly learn later on the actual mechanisms, yet in both instances we produce one chemical which is an alcohol and the various other chemical will be a carboxylic acid once esters are hydrolyzed. Third, we will certainly develop an ester. It need to be detailed that ester formation cannot happen in the existence of base, only acid. Throughout the first day of this lab, we will produce salicylic acid. This acid will then be provided to make aspirin. The synthesis of aspirin is a multi-billion dollar a year chemical. While salicylic acid as some therapuetic worth, it is not as effective as aspirin in reducing inflammation and also various other prevalent clinical problems for which aspirin deserve to be used. Aspirin is part of a large group of chemicals classified as Non-Steriodal Anti-Inflammatory Drugs (NSAIDS).

Procedure

This experiment is written of two components. The first requires the hydrolysis of methyl salicylate in order to produce salicylic acid (Day 1). The salicylic acid produced in this component of the experiment will certainly be offered to prepare acetylsalicylic acid (aspirin) (Day 2). The aspirin must be extremely pure, so you will execute a second purification of the aspirin on the third day.

Day 1: Hydrolysis of Methyl Salicylate

Many esters have actually acquainted odors. Methyl salicylate, an ester acquired from the combination of salicylic acid and methanol, is additionally known as the oil of wintergreen. Methyl salicylate was first isolated in pure develop in 1843 by extractivity from wintergreen plant (Gaultheria). It was shortly uncovered that this compound had analgesic and also antipyretic character almost the same to that of salicylic acid once taken internally. This medicinal impact more than likely outcomes from the ease with which methyl salicylate is hydrolyzed to salicylic acid under the alkaline problems uncovered in the intestinal tract. Methyl salicylate have the right to be taken internally or absorbed via the skin, for this reason its use in some liniment preparations. When applied to the skin, it produces a mild burning or soopoint sensation, which is probably because of the action of its phenolic hydroxyl group. Methyl salicylate also has actually a pleasant odor, and it is supplied as an extract for flavoring functions. Esters can be hydrolyzed right into their carboxylic acid and alcohol components under either acidic or basic problems in the presence of heat. In this experiment, methyl salicylate, an ester also well-known as oil of wintergreen because of its herbal resource and also odor, is treated with aqueous base and heated. Because, in our experiment, hydrolysis occurs in the existence of base (instead of acid), the carboxylic acid and also phenolic -OH groups on salicylic acid are ionized and also this compound exists as the sodium salt of salicylic acid, sodium salicylate. The reaction mixture is subsequently acidifed utilizing sulfuric acid, which converts this anion right into the totally protonated acid, salicylic acid. The alcohol is methanol. The salicylic acid, which is mostly insoluble, is a solid and have the right to be isolated and also purified by crystallization. The chemical equation that explains this experiment is: As stated over, the phenolic hydroxyl team, which is likewise acidic, would certainly be ionized and also exist as the sodium salt in the time of the fundamental hydrolysis, just choose the carboxylic acid group, but it is not shown ionized in this number bereason we are concerned through the ester hydrolysis. As the complying with figure shows, the phenolic -OH, as well as the carboxylic acid group, will certainly be protonated throughout the acidification action complying with the addition of the sulfuric acid. The following figure reflects what happens during acidification: The hydrolysis of methyl salicylate will be percreated utilizing the following setup.Obtain around 25 mL of freshly prepared 5 M NaOH (or, alternatively, you have the right to dissolve 5.0 g of sodium hydroxide pellets in 25 mL of water). Pour right into a 100-mL round bottom flask (always use a funnel; never before pour chemicals through a ground-glass opening).Add 7.5 g (0.050 mol; 50 mmol) of methyl salicylate (a liquid) to the 100-mL round-bottomed flask containing the NaOH. (a white solid might form, however it will disfix easily when the mixture is heated.)Add ~3-4 boiling stones to proccasion bumping (which is the manufacturing of a huge gas bubble once heated) or unalso boiling. Attach a reflux condenser to the optimal of the flask and also revolve on the cooling water. Heat the reactivity mixture to boiling using a heating mantel. Allow the mixture to reflux (via cooling) for about 20 minutes. The liquid mixture have to be continually boiling for the whole reflux time. After a 20 min reflux, transfer the reactivity mixture to a 250-mL beaker. Add 50 mL of DI water to the reaction contents in your beaker.Either include a stirring bar or intensely stirr the solution through a glass stirring rod as you add acid in the next step.Carecompletely include enough 3 M H2SO4 to make the solution acidic to litmus paper (pHydroin paper) to a pH of 1. Note: It is ideal to include the acid progressively with stirring to mix the contents fairly than simply pouring the acid right into the beacker. Stirring and adding gradually should proccasion sodium salicylate from becoming entrapped in the solid salicylic acid.You might must add even more than 25 mL of 3 M sulfuric acid (for example, you will need even more than 20 mL simply to neutralize the NaOH supplied in the reaction). Solid salicylic acid must develop as the neutralization proceeds. After pHydroin paper shows a pH of 1, add 1-2 mL more of the 3M sulfuric acid to encertain all the salicylic acid precipitates. The mixture will be acidic, however as well much acid will not be a problem: Acid stays acid in acid!Cool the mixture in an ice-water bath to around 0oC. Let beaker continue to be in the ice bucket for around 15 min while permitting the crystals to clear up.The salicylic acid have to have to be a slurry prior to you execute the filtration. So, if the solid is not openly flowing in the beaker, add sufficient water so that the solid is suspfinished and a liquid slurry appearance.Collect the crystals by vacuum filtration, using a Büchner funnel and filter paper. The filtration have the right to be performed many easily by decanting off the majority of of the supernatant liquid through the Büchner funnel prior to adding the mass of crystals. Carecompletely wash the beaker via ice cold water, if important, to deliver all the crystals to the funnel. Store the salicylic acid crystals in an evaporating dish or beaker in the drying oven until the next lab duration. Since your built up crystals from an acid solution, you cannot keep your filter paper via your chemical.

STOP AND STORE THIS PART OF THE EXPERIMENT UNTIL THE NEXT LAB PERIOD!

Day 2: Procedure for the preparation of aspirin

When the crystals are thoapproximately dry, weigh them and recognize the percent yield, based upon the amount of beginning material. Remember, 1 mol of methyl salicylate returns 1 mol of salicylic acid). Determine the melting allude of your purified salicylic acid (m.p. 159-160oC) and compare it to a sample of pure salicylic acid from the stockroom. Aspirin is a trade name for acetylsalicylic acid, a prevalent analgesic. Acetylsalicylic acid is an acetic acid ester derivative of salicylic acid. The earliest well-known uses of the drug have the right to be traced earlier to the Greek doctor Hippocrates in the fifth century B.C. He supplied powder extracted from the bark of willows to treat pain and reduce fever before. Salicin, the parent of the salicylate drug family members, was effectively isolated in 1829 from willow bark. Sodium salicylate, a predecessor to aspirin, was arisen along with salicylic acid in 1875 as a pain reliever before. Sodium salicylate was not frequently renowned though, as it has actually a halittle bit of irritating the stomach. However, in 1897, a man called Felix Hoffguy changed the face of medicine forever before. Hoffguy was a Germale chemist working for Bayer. He had actually been using the widespread pain reliever before of the moment, sodium salicylate, to treat his father's arthritis. The sodium salicylate brought about his father the very same stomach trouble it caused various other people, so Felix chose to attempt and also concoct a much less acidic formula. His occupational caused the synthesis of acetylsalicylic acid, or ASA. This quickly came to be the pain killer of choice for doctors around the world. Scientists never really taken the inner wormonarchs of the drug but. It wasn't till the 1970's, as soon as British pharmacologist John Vane, Ph.D. began work on aspirin that people started to understand also how aspirin really works. Vane and his colleagues found that aspirin inhibited the release of a hormone prefer substance referred to as prostaglandin. This chemical regulates certain body attributes, such as blood vessel elasticity and also changing the features of blood plateallows. Therefore can aspirin affect blood clotting and also ease inflammation. The reactivity for synthesis of acetylsalicylic acid is displayed in the adhering to figure. Salicylic acid, all set from the hydrolysis of methylsalicylate is reacted through acetic anhydride producing the ester product, acetylsalicylic acid. In a previous experiment, we have actually used the Fischer esterification reactivity to develop isopentyl acetate from an acid (acetic acid) and also an alcohol (isopentyl alcohol). The present experiment provides the carboxylic acid derivative, acetic anhydride, for ester development. The advantage of utilizing acetic anhydride is that you perform not create water which can be offered for hydrolysis of the recently formed ester. Concentrated sulfuric acid will be offered to save every little thing in the protonated state. Acetic anhydride is the desired acid derivative to synthedimension aspirin commercially bereason the acetic acid produced in this reactivity (a reactivity by-product) can be provided again, by converting it earlier into acetic anhydride. If you reextended much less than 3.5 g of salicylic acid, you will certainly should change the amounts of reagents used inthis protocol. However before, if you recovered at leastern 3.5 g salicylic acid, use the amounts of reagents provided below (remember, if you recovered more than 3.5 g of salicylic acid, use only 3.5 g salicylic acid regardmuch less of just how a lot you recovered). If you recovered less than 3.5 g salicylic acid, just propercentage the quantities of the various other reagents for this reaction. Initiate the aspirin synthesis reaction: Preheat 60-90 mL of water in a 400-mL beaker to boiling. Place about 3.5 g of salicylic acid right into a 125-mL Erlenmeyer flask (perform no use more salicylic acid, even if you isolated more)Add 3.5 mL of acetic anhydride (density is 1.08 g/mL) using a pipettor (if you reset the pipettor to a various value, please recollection it back to the 3.5 mL value so various other students don"t use the wrong amount).Add around 4 or 5 drops of focused (18 M) sulfuric acid to the mixture (some warmth might be generated). This addition of acid permits the carbonyl carbon of acetic anhydride to be more electrophilic.Heat the flask containing your reactants by placing it right into a beaker of boiling water for 5 or six minutes. Stir the mixture by gently swirling the flask. Throughout this time, the solid have to disresolve entirely. Isolation of aspirin Rerelocate the flask from the boiling water bath, and include 15 mL of ice water to it. (The ice hydrolyzes the unreacted anhydride and also keeps the mixture cool. Can you create the equation of this hydrolysis reaction?)

Thoapproximately cool the flask to complete the initial crystallization of aspirin. Remember that when a solution becomes cloudy, that is a solid developing and also this would certainly be the crystals of aspirin you desire. If crystals are sluggish in developing, you might need to scrape the inside of the Erlenmeyer flask through a glass rod, which will rate up crystal formation by seeding, or initializing the formation of crystals. Collect your aspirin via vacuum filtration, and let air proceed to be attracted over the solid for about 10 minutes to evaporate the majority of of the water bordering the solid.

The aspirin product will be analyzed utilizing HPLC (High Pressure Liquid Chromatography). The HPLC resolves the aspirin from the salicylic acid. For your evaluation, weight out exactly 0.0100 grams of sample and area in a clean test tube. To this test tube, add five mL methanol, and swirl to disdeal with aspirin. Then, include 5 mL Milli-Q water (ultra purified) to facilitate disresolving. This liquified material will be given to an IA that will run your sample on the HPLC and offer you a copy of the chromatogram of your crude aspirin.

Characterization of aspirin by re-crystallization and also solubility

Take about 2 grams of your slightly moist aspirin isolated above and include to a little beaker. Add either 5 mL of methanol or 5 mL of acetone and gently swirl to disfix the solid. You might should heat slightly, however carry out not boil the mixture. All of the aspirin need to dissolve in the warmth solvent. Remove the beaker containing the aspirin-solvent mixture and also let it cool to room temperature on the bench. When it is about room temperature (the beaker will certainly feel slightly cool to the touch), place the beaker in an ice bucket to proceed to develop crystals. After about 15 minutes on ice, collect by vacuum filtration your crystals (carry out not use water to wet the filter paper, but usage the very same solvent to wet the filter paper prior to collecting crystals).

Let the vacuum continue to be drawn via the Buchner funnel for around 15 minutes to thoapproximately evaporate the solvent.

At this allude, your filter paper and your crystals need to be dry. Weigh your sample to recognize your yield of re-crystalized aspirin. For HPLC evaluation of your re-crystallized aspirin, weigh out around 0.0100 grams of your re-crystalized aspirin and add 5 mL of the anhydrous methanol, dissolve and also then add 5 mL Mili-Q water to disfix your solid. Slight warming should not be crucial.

Do a yield, percent yield, and also melt temp of your re-crystallized aspirin. Be sure to have your aspirin samples analyzed via HPLC.

Caution: Aspirin decomposes in boiling water (therefore, carry out not boil the aspirin) or once liquified in solutions of alkali hydroxides and carbonates. Inorganic salts of acetylsalicylic acid are soluble in water (especially the Calcium salt, but are decomposed conveniently.

An alternate re-crystallization procedure could encompass one of the adhering to options:The purpose of re-crystallization is to eliminate contaminating chemicals, such as salts. So, also if you do not completely dissolve all your aspirin, you might still impact a purification by including a details amount of water. After adding some water (e.g., approximately 100 mL water), heat the mixture up to50-60oC and let as a lot aspirin disfix as possible. Then, cool the mixture and also let the crystals create, even though not all the solid might have actually gone solution. This method efficiently washes the crystals and lets the contaminants gain diluted into the solvent. After cooling, collect the crystals by vacuum filtration.You have the right to take advantage of the high solubility in one solvent and the lower solubility in an additional. For instance, if your solid dissolves easily in ethanol, yet not well in water (check the solubilities above), initially disfix your solid in as little bit ethanol as feasible, possibly at a slightly elevated temperature. Then, include a big excess of water (e.g., 100 mL of water), and also let your sample stand on ice for 10-15 min. Collect the crystals as normal.

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Analysis of product.

What is the yield of dry aspirin? What is the percent yield? What is the melt point? (The crystals may have actually a large melting selection, from 125-138oC, bereason of potential of decomplace. The usage of a preheated melting allude gadget (heated to about 110oC) will help to minimize this decomplace. Why do you think this could assist proccasion decomposition?)

Chemicals, Reagents, and also Supplies Compound MW Amount mmol mp bp Density ηD msds Methyl salicylate 152.15 6.4 mL (7.5 g) (usage pipettor) 49.3 -8.6 223.3 1.184 msds Salicylic acid 138.12 3.5 g 25.3 159 211 1.44 msds Acetyl salicylic acid (aspirin) 180.16 135 140 1.35 msds Acetic anhydride 102.09 3.5 ml (use pipettor) -73.1 139.9 1.08 1.389 msds NaOH (5 M) 40.0 25 mL 125 msds H2SO4 (6 M) for Day 1 98.0 8-10 mL msds H2SO4 (18 M) for Day 2 98.0 a couple of drops msds Compound g/mol grams or mL 10-3 mol oC oC g/mL ηD msds