Lab B - Synthesis of Aspirin

Phosphoric acid

*Very corrosive -Blue diamond = 3 -Red diamond = 0 -Yellow diamond = 2 -White diamond = ACID

Developing chamber to run a TLC plate

*Watch glass on top! -250 mL beaker -TLC plate at an incline -Baseline of the TLC plate should be well above the solvent front in the beaker -Eluent at the bottom (eluting solvent) -Paper towel is used to saturate the atmosphere inside the beaker with the solvents

National Fire Protection Association (NFPA) Ratings

-4 diamonds - blue, red, yellow, and white -Blue: Health hazard 4 Deadly 3 Extreme danger 2 Hazardous 1 Slightly hazardous 0 No health threat -Red: Fire Hazard Flashpoints 4 Below 73 F 3 Below 100 F 2 Below 200 F 1 Above 200 F 0 Will not burn -White: Specific Hazard W - Water reactive OX - Oxidizing agent ACID - Acid CORR- Corrosive -Yellow: Reactivity hazard 4 May detonate 3 Shock or heat may detonate 2 Violent chemical reaction; water reactive 1 Unstable if heated 0 Stable

Carcinogen

-A carcinogen is a substance that is capable of causing cancer -Examples: Benzene, arsenic, asbestos

What are the characteristics of a good recrystallization solvent?

-A good recrystallization solvent dissolves the sample when it is hot, but does not dissolve the sample at room temperature/when it is cold -Also, solubility in the solvent should not be too high, because this makes recrystallization more challenging

Lachrymator

-A lachrymator is an irritant that causes tearing (watering of the eyes) -Some examples of lachrymators - Thioyl chloride, acrolein, methacryloyl chloride

Teratogen

-A teratogen is a drug or other substance capable of interfering with the development of an embryo fetus that may lead to birth defects or developmental malformations -Examples of teratogens - phenol, benzene, dinitrotoluene, dioxane

Hydrolysis of acetic anhydride (see slide 4!)

-Acetic anhydride is a symmetrical molecule -Hydrolysis is how excess acetic anhydride is eliminated

Analysis of a thin layer chromatogram

-Ratio to the front (Rf) or ratio of distances -Rf = Distance traveled by compound (or SOLUTE)/Distance traveled by solvent front (or ELUENT)

Bromine

*Extremely corrosive -Blue diamond = 4 -Red diamond = 0 -Yellow diamond = 0 -White diamond = OXY

Acetone

*Flammable -Blue diamond = 1 -Red diamond = 3 -Yellow diamond = 2 -White diamond = nothing

Procedure - Synthesis of Aspirin

*Review calculations on pages 9 and 10 of lab notebook 1. Obtain mass of dry salicylic acid. Do reaction using 90% of that salicylic acid. Calculate amount of acetic anhydride needed (amount of salicylic acid times 3) 2. Transfer 90% of salicylic acid into a 50 mL Erlenmeyer flask 3. Obtain acetic anhydride that you need for your reaction in your 10 mL graduated cylinder. Add acetic anhydride to your Erlenmeyer flask, then add 5 drops of 85% phosphoric acid (made reactant turn yellow). Loosely stopper (with a cork stopper) the Erlenmeyer flask 4. Let reaction stand for 10 minutes, then heat reaction in a warm water bath for 10 minutes. Solution became homogeneous/yellow 5. Chilled mixture in an ice water bath while scratching the inside of the flask with a glass rod. A yellow/white paste forms. Add 10 mL of cold water and 10 mL of ice to the Erlenmeyer flask and stir. Observed that paste turned white 6. Collect the crystals in a Buchner funnel with vacuum filtration. Empty the solution from the filter flask and draw air over the crystals. The crystals should be colorless/white, but it is okay if they are slightly yellow. Observed that crystals appeared powdery and white *Acetic acid/water solution should be neutralized with sodium bicarbonate (NaHCO3) 7. Recrystallize compound from water. Solvent used was water. Knew because the compound did not dissolve in water. 8. Boil water on the hot plate and dissolve aspirin using a minimum amount of boiling solvent until all of the aspirin is completely dissolved (homogeneous solution). Bring the solution to a boil quickly and limit the amount of time you are boiling the crystals in the solvent 9. Let flask cool slowly inside the hood on the bench top until crystal formation occurred. Observed that crystals were clear and spiky 10. Collected crystals by vacuum filtration again. Crystals appeared shiny, clear, and needle-like 11. Conducted aqueous FeCl3 test on both the salicylic acid (control) and the aspirin. Put each compound in a test tube, added about 1 mL of ethanol, and added 3 drops of 0.02 M aq FeCl3. Purple = traces of salicylic acid. Aspirin should have no purple/be only faintly purple -All of the solutions from the aqueous FeCl3 tests must be poured into the "Aq FeCl3 waste" container *Used glass pipettes must be disposed of into the red sharps container

Acetic anhydride

-Acetic anhydride is two molecules of acetic acid (one of the components of vinegar) with a molecule of water removed -The reaction is an equilibrium reaction, and an excess of acetic anhydride is required to drive the reaction toward completion -The excess of acetic anhydride also serves as the solvent for the reaction

Other medicinal compounds with ester functional groups (see slide 5)

-Benzocaine (topical anesthetic) -Maxicaine (local anesthetic) -Demerol (narcotic analgesic)

Theoretical yield of aspirin

-Calculate the amount of aspirin you could ideally produce (theoretical yield) -Theoretical yield is based on the stoichiometric amounts of reactants in the balanced equation and the limiting reagent

Corrosives

-Corrosives are materials that can attack and chemically destroy body tissues, causing chemical burns -Most corrosives are strong oxidizers and they are either acids or bases -Examples of corrosives - H2SO4, NaOH, HNO3, Ca(OH)2, Br2, phosphoric acid)

Flammable

-Flash point is the lowest temperature at which a liquid can form an ignitable mixture in the air near the surface of a liquid -The lower the flash point, the easier it is to ignite the material -For example, gasoline has a flash point of approximately -40 degrees C and is more flammable than ethylene glycol (antifreeze), which has a flash point of 111 degrees C

Gravity filtration

-Gravity filtration is used for a low-boiling organic (CH2Cl2, diethyl ether, etc.) -Gravity filtration is used to filter drying agents such as anhydrides and MgSO4 -You used a powder funnel (short-stem funnel) for gravity filtration. The powder funnel is placed in a ring and has a filter paper cone inside -The hot solvents contains insoluble material

TLC plate

-Has a smooth side and a rough side. The rough side is silica gel -Using a pencil/ruler mark 1 cm. from the bottom -Do not put any breaks in the TLC plate -Bottom line = baseline, top line = solvent front -Handle the TLC plate by the edges and place at an incline in the beaker with tweezers -Make small, dilute spots!

Mel-Temp

-Impurities increase the melting point range and lower the melting point -Start recording the melting point when you first see the sample begin to collapse away from the walls of the capillary tube. A meniscus will appear -Finish when there is complete disappearance of solid material

Aspirin background information

-In 1875, a scientist working for Bayer tried to modify the OH group of salicylic acid into a different functional group -Aspirin was patented by Bayer in 1893 -Aspirin is one of the oldest and most consumed drugs - production in the US is 10 million kg of aspirin per year! -Aspirin moves through the body until it reaches the small intestine. Then, it is released into the blood stream and has pain-relieving effects

Two-step reaction

-In a two-step reaction, the amount of product that you isolate from the first reaction will determine the amount of starting material that you have for the second reaction -Frequently do not use all of your material in the second reaction in case the reaction doesn't work (90% in this case)

Synthesis of aspirin

-In the synthesis of aspirin, you will treat salicylic acid with acetic anhydride -In order to proceed, the reaction requires an acid catalyst - phosphoric acid -In this lab, we will be using 90% of our salicylic acid to synthesize aspirin -At the end of the aspirin reaction, we will be able to isolate the product by doing a vacuum filtration and then purify it by recrystallization -Determine if there is any leftover salicylic acid in your aspirin by treating both the crude and recrystallized aspirin with a solution of FeCl3.

Sources of chemical information

-MSDS sheets -Merck Index -Aldrich catalog

Merck Index: Chemical information for phosphoric acid

-Molecular formular: H3O4P -Molecular weight: 98.00 -d25 (density at 25 degrees Celsius) = 1.8741 (100% solution), 1.6850 (85% solution), 1.3334 (50% solution), 1.0523 (10% solution) -Phosphoric acid is corrosive - miscible with water and alcohol. Sol in 8 vols of a 3:1 ether: alcohol mixture

Purity check with aqueous FeCl3 solution

-Phenols react with FeCl3 (aq) to produce a deep purple complex -In a test tube, separately test a small quantity of salicylic acid (as a control) and recrystallized aspirin with 1 mL of ethanol each and 3 drops of 0.02 M aq FeCl3 solution -A purple colored solution indicates the presence of a phenolic OH group, hence traces of salicylic acid present in the product -Conclusion - qualitatively, this test indicates the presence of unreacted starting material in your final product -Salicylic acid is dark purple -Aspirin is not purple or faintly purple

Equivalents

-The amount of acetic anhydride you need depends on the amount of salicylic acid that you isolated -We use the concept of equivalents, which is the experimental ratio in which reactants are added to the reaction -While the stoichiometric ratio (which is used to calculate the percent yield) in which acetic anhydride and salicylic acid react is 1:1, we need to use more moles of acetic anhydride than of salicylic acid in order to drive the equilibrium *3.0 equivalents of acetic anhydride to 1.0 equivlent of salicylic acid (3 times the number of moles of acetic anhydride compared to salicylic acid)

Stoichiometric ratio

-The stoichiometric ratio is used to calculate the percent yield -Acetic anhydride and salicylic acid reaction is in a 1:1 ratio -However, the reaction has been previously optimized by experimenters using 3.0 equivalents of acetic anhydride to 1.0 equivalent of salicylic acid (or three times the number of moles of acetic anhydride compared to the moles of salicylic acid)

Reaction scheme for the synthesis of aspirin (see slide 4)

-The synthesis of aspirin is an example of an esterification reaction because you add an ester group (C=OCH3) to the benzene ring of salicylic acid

What is thermometer lag? How will this affect your melting points? How can you avoid thermometer lag? What is another problem with determining your melting point too quickly?

-Thermometer lag occurs when the heating block's temperature increases so quickly that the temperature of the sample cannot keep up. -This will make the melting points appear LOWER than they really are -You can avoid thermometer lag by melting the sample slowly -Another problem with determining the melting point too quickly is that it makes it hard to tell when the sample has started and ended melting. Also, the melting point range will seem broader than it really is.

Reactive

-Things that go BOOM -Examples of reactive - Na metal, sodium hydride, calcium carbide

Why do you do this reaction in an Erlenmeyer flask rather than a beaker?

-This reaction is done in an Erlenmeyer flask because there is less evaporation from the flask than from a beaker -It also prevents the solid from climbing the walls of the beaker

Vacuum filtration

-Vacuum filtration is used for high-boiling organics (alcohol and hydrocarbon solvents) and water -Use a Buchner funnel. Paper covers all holes, but does not come up the sides -Pour crystals in solvent on top of the filter paper -Rubber stopper, clamp, connected to vacuum trap. On top of a ring stand for support *Vacuum filtration should NOT be used for volatile (or low-boiling) solvents, as the solvent will evaporate during the filtration and contaminate the product crystals with impurities that have just been removed

Safety precautions

-Wear your safety goggles and gloves at all times in the lab -Acetic anhydride is irritating to the nose. Keep this compound inside the hood at all times, and avoid breathings its vapors

Using a hot plate

-When you are not using the hot plate, unplug it! -Before turning the heat on the hot plate, push the red vacuum tubing to the back wall of the fume hood

Problem with recrystallizing aspirin

-You need to be careful when recrystallizing aspirin -Aspirin will react with water to revert to salicylic acid -Boiling the water for extended periods of time and having phosphoric acid that was not removed in the first filtration will both speed up this process

Drying your product

-Your product is wet, even after vacuum filtration! -Transfer the product to a watch glass, break down big clumps of the product, and leave it to air dry -Weigh the wet and dry masses *Characterization of aspirin = determination of melting point

Calculate the volume of acetic anhydride needed for the synthesis of aspirin

0.90 * (X grams salicylic acid/molecular weight of salicylic acid) * (3 mol acetic anhydride/1 mol salicylic acid) * (Molecular weight of acetic anhydride/Density of acetic anhydride) = Z mL of acetic anhydride

Biological activity of aspirin

1. Analgesic - relieves pain 2. Antipyretic - reduces fever 3. Anti-inflammatory

Thin Layer Chromatography - 4 steps

1. Application of sample - capillary (open on both ends) is used to spot the solution of each sample 2. Development of sample - this is when the separation actually occurs 3. Visualization of the sample - our result will be viewed under UV light 4. Interpretation of results - comparison of retention factors

Sample application (spotting)

1. Draw a baseline about 1 cm from the bottom of the TLC plate 2. Draw guidelines for the spots gently with a pencil 3. Use a different TLC capillary tube to transfer and spot each compound. Spot lightly

Reagent table

1. Salicylic acid -Molecular weight = 138.12 g/mol -Equivalent = 1 2. Acetic anhydride -Molecular weight = 102.09 g/mol -Density = 1.08 g/mL -Equivalents = 3 -Boiling point = 139.8 degrees C 3. Phosphoric acid -Volume = 5 drops -Hazards = corrosive

Molecular weight of aspiring

180.16 g/mol

Chemical toxicity

6 different classes of compounds: 1. Flammable (low flash point) 2. Corrosives 3. Lachrymator 4. Carcinogen 5. Teratogen 6. Reactive *Could be on the test as definitions or examples

Acids

Acids have smaller Rf values

Actual yield of salicylic acid

Actual yield = Dry mass of salicylic acid = X grams of salicylic acid

Waste disposal procedure

All organic waste must be placed in the RED organic waste containers. Ensure that your waste is disposed of correctly either in the "Non-halogenated" or "Halogenated" waste containers -"Non-halogenated"- chemicals containing ONLY C, H, and O -"Halogenated" - chemicals containing C, H, O, and halogens Any waste generated from either acid or base must first be neutralized with NaHCO3 and then poured down the sink

Equivalent

An equivalent is the EXPERIMENTAL ratio in which reactants are added to the reaction

Overall percent yield for aspirin synthesis

Overall percent yield - (% yield from Lab A)(% yield from Lab B) * 100

Experimental details of the synthesis of aspirin

How much of the reagents should you use? -Use 90% of the salicylic acid (SA) that you synthesized -Use 3 equivalents of acetic anhydride to drive the equilibrium reaction -Use 4-5 drops of concentrated phosphoric acid (H3PO4) 1. Set up a 150 mL beaker with water to warm up on a hot plate (medium heat) 2. Transfer 90% of synthesized SA to a 50 mL Erlenmeyer flask 3. Bring a 10 mL graduated cylinder to get acetic anhydride 4. Ask TA for H3PO4, then loosely stopper the flask Left over salicylic acid: -Reserve a small amount for melting point analysis -Reserve a small amount of the purity test using aqueous FeCl3 solution

Percent yield of aspirin

Percent yield = (actual yield in grams/theoretical yield in grams) * 100

Theoretical yield of salicylic acid

Moles of methyl salicylate * mole ratio (Salicylic acid / Methyl salicylate) * Molecular weight of salicylic acid (g/ mol) = Y grams of salicylic acid

Small scale solvent test

Sample of aspirin (tip of spatula) in a test tube + 1/3 of test tube filled with solvent (H2O, C2H5OH - ethanol)

What are the rules for selecting a good solvent?

Soluble when hot and insoluble when cold

Dry mass of aspirin

The dry mass of aspirin is your actual yield of aspirin

What is the best method for purification of aspirin?

Water!

Percent yield of salicylic acid

X grams / Y grams * 100