Lab A & B - Synthesis of Aspirin

Physical State of Methyl Salicylate

Liquid

What does methyl salicylate smell like?

Mint

What functional-group change converts methyl salicylate into salicylic acid?

A methyl ester is converted into a carboxylic acid

What molecular change did Felix Hoffmann make to salicylic acid?

Phenol group into acetyl group

Aspirin Real Name

Acetylsalicylic Acid

What is the major advantage of aspirin over salicylic acid?

Less severe GI effects

What happens to salicylic acid at physiological pH?

Deprotonated to form salicylate

What reagent is traditionally used to detect salicylates?

Iron (III) Chloride (FeCl3)

What functional group reacts with FeCl3 to produce an effect, detecting salicylates?

Phenol group

What reagent is used to convert methyl salicylate to salicylic acid, and how does it do it?

- Sodium Hydroxide (NaOH)

- Converts an ester into carboxylic acid

Saponification

Conversion of an ester into a carboxylic acid

What is the advantage to using an Erlenmeyer Flask?

Sloped sides reduce solvent evaporation and loss from splashing

What are the hazards of NaOH (sodium hydroxide)?

Corrosive

What are the hazards of HCl (hydrochloric acid)?

Corrosive

What species of salicylic acid forms in excess NaOH?

A very water-soluble disodium salt

What is required to "regenerate" salicylic acid after adding NaOH, and how does our experiment do this?

- Need to lower the ph below 3 (re-generate the COOH)

- Use 6M HCl

What happens when 6M HCl is added to the disodium salicylate?

The H+ protonates the oxygen anions, and forms NaCl as a byproduct

What are the byproducts of the synthesis of salicylic acid, and where do these byproducts go?

Byproducts: Methanol, Water, NaCl

Stay dissolved in solution

Why does the salicylic acid precipitate during acidification? Why do the byproducts stay dissolved?

Protonated salicylic acid is not very water-soluble, while the products are

Recrystallization

Purification method where an impure solid is dissolved in hot solvent, then crystallized during cooling

What happens to impurities that are insoluble at high temperatures?

They get removed by hot-gravity filtration

What happens to impurities that are soluble at low temperatures

They tend to remain in the mother liquor

Mother Liquor

Solution from which a substance has crystallized or precipitated

How much water dissolves 1 g salicylic acid at low temperature?

460 mL

How much boiling water dissolves 1g salicylic acid?

15 mL

Why do solubility differences make recrystallization effective/

Product dissolves hot, lets out all impurities, and crystallizes as the solution cools

What reagent reacts with salicylic acid to produce aspirin?

Acetic anhydride

Dangers of Acetic Anhydride

- Flammable

- Corrosive

Acetic Anhydride

Two molecules of acetic acid w/ a molecule of water removed

What functional group is modified in the synthesis of aspirin from salicylic acid?

Phenol group is acetylated

Acetylation

Addition of an acetyl group

Explain the implications of the synthesis of aspirin being an equilibrium reaction.

Excess acetic anhydride is needed to drive the equilibrium towards aspirin formation

What catalyst is used to create aspirin from salicylic acid?

H3PO4 (phosphoric acid)

What are the byproducts of the synthesis of aspirin from salicylic acid?

Acetic acid

What is the stoichiometric ratio of salicylic acid to acetic anhydride? How many equivalents are used to drive the reaction towards the formation of aspirin?

1:1

3 mol acetic anhydride:1 mol aspirin

Which is the better recrystallization solvent for aspirin, water or ethanol? Why?

Water; aspirin is nonpolar and won't dissolve in water at room temperature

What defines a good recrystallization solvent?

Solute is insoluble at cold/room temperature, but soluble in warm/hot temperatures

What is used to test for leftover salicylic acid in the aspirin?

Iron (III) Trichloride (FeCl3)

Why does FeCl3 turn purple for salicylic acid but not for aspirin?

Salicylic acid has phenol group that FeCl3 reacts with

What conditions accelerate aspirin hydrolysis in water?

- Prolonged boiling

- Residual phosphoric acid

Why is hydrolysis not good for aspirin?

Converts it back to salicylic acid

What is the first thing added to the methyl salicylate? Why?

NaOH

Provides strong basic conditions to hydrolyze methyl salicylate

What reaction does methyl salicylate undergo with NaOH?

Saponification (base-promoted ester hydrolysis)

What does the saponification of methyl salicylate create?

Salicylate & Methanol

What compounds are present initially after NaOH is added?

Methyl salicylate, NaOH, water, salicylate/product intermediates, and methanol

Why do we heat the mixture after the addition of NaOH?

Heating increases the rate of ester hydrolysis.

What is the initial white precipitate seen immediately after adding NaOH?

It is an initial solid formed in the basic reaction mixture; it is not the isolated salicylic acid product

After adding NaOH, what happens to the cloudy mixture as heating continues?

It becomes clear and homogeneous; the previously solid intermediate has dissolved into the mixture

Why does the solid dissolve during heating after adding NaOH?

Increased temperature and reaction progress allow the material to enter solution.

How do you confirm boiling?

Turn stirring off, look for raging boil

What is the desired product during the NaOH reaction?

Salicylate ion, the deprotonated form of salicylic acid.

What happens chemically to the salicylate ion while the solution cools after adding NaOH?

Nothing new, just prepping it for the addition of HCl

- Stays in solution because the solution is still very basic

What is the purpose of adding HCl to the salicylate ion solution?

- H⁺ protonates the carboxylate group.

- Forms neutral salicylic acid

Why does salicylic acid precipitate?

Neutral salicylic acid is much less soluble in water than ionic salicylate.

What is the white precipitate after HCl addition?

Salicylic Acid

What is still in solution after salicylic acid precipitates?

Water, excess acid, Na⁺, chloride, methanol, and other dissolved species.

Why is HCl added incrementally? Why do we stir after each addition?

To control the acidification and observe when precipitation is complete.

Why do we want the solution to be acidic (after adding HCl)?

Acidic conditions ensure the salicylate has been protonated into salicylic acid.

What is in the flask immediately before filtration, right after adding HCl?

- Solid salicylic acid

- Water, excess NaCl, methanol

Why do you wet the Buchner funnel?

Water helps seal the paper against the funnel so liquid does not bypass it.

Why do we recrystallize, even after filtration?

Filtration separates solid from liquid but does not remove impurities trapped in or associated with the solid.

What property of salicylic acid makes recrystallization possible?

Salicylic acid is much more soluble in hot water than cold water.

Why does salicylic acid dissolve in hot/boiling water?

Higher temperatures provide the thermal energy needed to overcome the strong intermolecular forces holding the solid molecules together

What happens to insoluble impurities during the hot/cold recrystallization of salicylic acid?

They remain undissolved and can potentially be separated from the dissolved product.

During recrystallization of salicylic acid, what happens as the solution cools?

Salicylic acid becomes less soluble and begins forming crystals.

Why do impurities often remain in the liquid instead of crystallizing?

They remain sufficiently soluble in the cold solvent.

Why is longer cooling better for recrystallization?

Longer cooling allows the molecules to arrange in more complex patterns

What do pure salicylic acid crystals look like?

White, needle-shaped crystals.

What is present after the recrystallization of salicylic acid?

Solid salicylic acid crystals suspended in liquid water containing dissolved impurities.

What is primarily in the filtrate during the second filtration of salicylic acid?

Water and dissolved impurities.

What is in the filtrate from the first filtration?

Water, excess acid, dissolved salts, methanol, and other soluble materials.

What do you use to neutralize acid waste?

NaHCO3

What is the first step of aspirin synthesis from salicylic acid?

Addition of acetic anhydride

What do you add in aspirin synthesis directly after acetic anhydride?

Phosphoric Acid (H3PO4)

Why is phosphoric acid added after the acetic anhydride?

It is added to catalyze the acetylation reaction once the reactants are together.

What is the purpose of the warm water bath while salicylic acid and acetic acid are mixed?

It supplies controlled heat to help drive the aspirin-forming reaction.

What is in the homogeneous solution that contains salicylic acid and acetic anhydride after heating?

Aspirin, acetic acid, excess acetic anhydride, phosphoric acid

Why do you cool the homogeneous mixture of aspirin and acetic anhydride after heating?

Cooling reduces the solubility of aspirin and promotes its precipitation/crystallization.

Nucleation

The initial stage in a phase transformation. It is evidenced by the formation of small particles (nuclei) of the new phase that are capable of growing.

Why does "scratching" the flask promote crystallization?

It creates sites where molecules can begin to organize into a crystal rather than remain randomly dispersed in solution.

What should form after cooling and scratching? What is it?

- A white, yellow, or yellowish-white paste.

- Precipitated/crystallized crude aspirin containing aspirin plus impurities.

Why is the solution allowed to further cool after the discovery of the paste?

Cooling helps to bring aspirin out of solution

What do you do after the paste has been cooling for a while?

Filtration to remove from solution

What does the filtrate from the yellow paste contain?

Water/acetic acid and other dissolved substances from the reaction mixture.

What do you do after filtering the yellow paste?

Recrystallization test (water)

After recrystallization, when should you place the flask in an ice water bath?

After substantial crystal formation is already visible during slow cooling.

After recrystallization, what two phases are present?

Solid purified aspirin crystals and liquid solvent containing dissolved impurities and some dissolved aspirin.

What passes through the filter during the second filtration of aspirin synthesis?

The recrystallization solvent containing dissolved impurities and some dissolved aspirin.

What generally happens to the melting point of an impure organic compound compared with a pure compound?

Impurities generally broaden and depress the observed melting range.

Where do you dispose of ethanol solutions?

C,H,O Non-Halogenated Contaienr

Where does waste from the aqueous FeCl₃ tests go?

The specially labeled aqueous FeCl₃ waste container.

What is our typical source of vacuum?

Compressor-driven Vacuum System

What do you look for during an MP test?

- First reading of the range - temperature at which the

solid block first begins to liquefy.

- Second reading of the range - temperature at which

the solid is completely melted.

What are the advantages of the DigiMelt?

- Rate at which the temperature of

the heating block increases can be programmed.

- You can input the Start temp., End Temp.,

and Ramp Rate.

Where do you put used MP tubes?

Glass Sharps

During an MP test, why should you increase the temperature slowly?

- Thermometer Lag - occurs when the sample melts before the thermometer has a chance to reach that temperature.

- Broad range observed when melting too quickly.

What is the difference between MP and TLC tubes?

MP closed on one end, TLC open on both ends

NFPA Designation: Methyl Salicylate

Blue (1)

Flammability (Red): 1

Instability/Reactivity (Yellow): 0

Special Notice (White): Blank

NFPA Designation: NaOH

Health (Blue): 3

Flammability (Red): 0

Instability/Reactivity (Yellow): 1

Special (White): COR

NFPA Designation: HCl

Health (Blue - Left): 3

Flammability (Red - Top): 0

Instability/Reactivity (Yellow - Right): 1

Special Hazard (White - Bottom): ACID