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Creating useful and beautiful molecules using synthetic organic chemistry –
Synthesis of Aspirin and Indigo
INTRODUCTION
Aspirin
Salicylic acid occurs naturally in the bark of willow trees. Prior to the 1800’s, willow bark was often brewed into a tea, or chewed to relieve pain. While the salicylic acid is effective at reducing pain it was found to irritate the lining of the stomach. It was mostly by chance that on August 10, 1897 Felix Hoffmann, a German chemist who obtained his PhD with Adolf von Baeyer (see below) and working at "Farbenfabriken vorm. Friedr. Bayer
& Co." made a discovery of historic significance. By acetylating salicylic acid with acetic acid, he succeeded in creating acetylsalicylic acid (ASA) in a chemically pure and stable form. Esterifying the salicylic acid to aspirin reduces the irritation of the stomach lining. The company developed a cost-effective production process that would allow the promising active ingredient to be supplied as a pharmaceutical product. In 1899, it was launched for the first time under the trade name Aspirin™. Today, aspirin is one of the most widely used medications in the world, with an estimated 40,000 tons being consumed each year.
Aspirin is a non-steroidal anti-inflammatory drug (NSAID) with a wide range of physiological effects. At very low doses, aspirin is used to treat and prevent heart attacks and blood clots. At higher doses it is used as an analgesic to reduce pain and as an antipyretic to reduce fever. At very high doses, it is an effective antiinflammatory agent used to treat rheumatic fever, gout and rheumatoid arthritis. It is also an anticoagulant, it dissolves corns and calluses, and it provokes loss of uric acid (a toxin) but promotes retention of fluids in the kidneys. It kills bacteria and induces peptic ulcers. The exact mechanisms of its pharmacological actions are still under study.
In this synthesis you will treat salicylic acid with acetic anhydride and a catalytic amount of sulfuric acid. The phenol OH group of salicylic acid will react with acetic anhydride to form the ester in aspirin. You are not responsible for the mechanism of this reaction, but are welcome to stop by to discuss it if you are interested.
O
C

O

OH
O

C

O

OH
H 3C

O

CH 3

catalytic H 2SO 4

OH
O
O

salicylic acid acetic anhydride O

CH 3

acetylsalicylic acid HO

CH 3

acetic acid

Figure 1. The synthesis of aspirin.
Indigo
The practice of using dyes from plants to dye fabric has been around for thousands of years. The blue dye indigo has been used in India to dye fabric for over 4000 years. The dye was derived from the plant Indigofera tinctoria. This dye spread from India to the Mediterranean and Europe by migrating peoples and traders. In the sixth century in France and in Germany, indigo was isolated from a plant known as “woad”. Johann Friedrich
Wilhelm Adolf von Baeyer, a German chemist (1905 recipient of the Nobel Prize in Chemistry), began work with indigo in 1865. Through his work, the first synthetic indigo was synthesized in 1880 and three years later the chemical structure was announced. This introduction of synthetic indigo met with violent opposition from growers of woad, and the use of synthetic indigo was prohibited in England, Germany, and France. The French king, Henry IV, even went so far as to issue an edict, condemning to death any one who used that pernicious
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drug called ‘devils food’. BASF developed a manufacturing method and by 1913 most nature indigo was replaced by synthetic indigo.
Denim, which uses indigo as a dye, has been around for centuries. Denim originated in the ancient textile centre of Nimes, France, and was called “serge de Nimes”. Columbus is reported to have used denim for his sails on the Santa Maria. At approximately the same time, in India, the sailors of Dhunga, were using denim material for their pants, which became known as dungarees. Later on the term “jeans” came into favor from
Genoa, Italy, where men wore denim work pants. In 1849, Levi Strauss, an unsuccessful miner in the
Californian gold rush in the USA, struck it rich by making denim pants for the more successful miners. Over the next hundred years, denim jeans have become a staple clothing item for people of diverse economic backgrounds. In this experiment, you will be synthesizing indigo using the Baeyer-Drewson reaction, shown below. This transformation is an example of an extremely important carbon-carbon bond forming reaction, the Aldol
Condensation. You will learn more about this in Chem 2320. For now you are not responsible for the mechanism. Please ask if you are interested.
O

O
H

2

NO 2

O

H 3C
CH 3 acetone NaOH

2-nitrobenzaldehyde

H
N

N
H

O indigo For the second part of this experiment, you will dye a piece of fabric with your synthetic indigo. To accomplish this task, the indigo must first be transformed into the water-soluble leuco-indigo by reduction with sodium hydrosulfite and sodium hydroxide. Why is leuco-indigo more water-soluble than indigo? In chemistry we refer to a reduction as the gain of electrons. In organic chemistry this often means the replacement of a bond to an electronegative atom such as oxygen or nitrogen with a non-electronegative atom like hydrogen. Can you identify the atoms that are reduced in indigo?
O

N
H

H
N

O

H
N

NaOH/Na 2S2O4
N
H

O

Indigo

O

Leucoindigo

The leuco-indigo, known as white indigo, will appear as a clear yellow solution. The fabric is emerged in this dye-solution. Once the fabric is lifted from the solution, the leuco-indigo comes into contact with the oxygen in the air and is oxidized back to the insoluble blue indigo, therefore coloring your fabric.
O

N
H

H
N

O

Leucoindigo

O

H
N

H 2O/O2
N
H

O

Indigo

The cloth which you use is a small square of a special fabric called Multifiber Fabric 10, which has the following patches of fibers woven into it: spun Rayon (cellulose acetate), cotton, a spun polyamide (Nylon 6,6),
Dacron, Orlon, and wool. You will probably find that the indigo will dye each fiber to a different extent, due to

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the different chemical composition of the various fibers. The structures of some of these fibers are shown below. EXPERIMENTAL - ASPIRIN
Equipment
Large beaker, hot plate, 50 mL Erlenmeyer flask, Graduated cylinder, Ring stand, Ice, Vacuum filtration apparatus Chemicals
Salicylic Acid, 2g
Acetic Anhydride, 5 mL
Sulfuric Acid, 5 drops
Ethanol, 10 mL

Waste Disposal eye and skin irritant, solid waste flammable, organic waste highly corrosive, aqueous acidic waste flammable, organic waste

Safety Notes
1. Salicylic Acid - can cause moderate chemical burns of the skin if at very high concentrations. Rinse with water for 15 minutes if skin or eyes are exposed.
2. Acetic anhydride – can cause severe chemical burns. In case of contact with the skin or eyes, let instructor know of incident and immediately begin rinsing with water for 15 minutes. Acetic anhydride is also a severe lachrymator. Handle in the hood at all times.
3. Ethanol – flammable. Avoid open flames.
4. Sulfuric Acid – can cause very severe burns, especially when it is at high concentrations. It is also strongly oxidizing. Rinse with water for at least 15 minutes if skin or eyes are exposed.

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Procedure
1) Fill a large beaker 1/2 - 2/3 full with water. Place on a hot plate and bring to a boil (do this right away – it takes a long time to boil water)
2) Combine the following in a 50 mL Erlenmeyer flask
a. 2 g Salicylic Acid (use a scale to weigh). Record actual amount to 2 decimal places.
b. 5 mL Acetic Anhydride (use a graduated cylinder to measure). Record the actual exact volume used.
c. 5 Drops of Concentrated Sulfuric Acid. Be extremely careful when handling. Use the plastic pipet from the bottle to deliver. Hold the pipet and
Erlenmeyer flask inside the hood at all times. This will minimize the possibility of the acid dripping on your legs/feet or floor. The floor will be permanently discolored if it comes into contact with sulfuric acid. Return the pipet back to the bottle. DO NOT carry the pipet across the lab.
d. Use a rubber stopper or orange septa to “cap” the Erlenmeyer flask before you take it out of the hood to minimize your exposure to the lachrymator acetic anhydride and the highly corrosive
H2SO4 fumes.
3) Clamp the flask with a utility clamp to a ring stand. Remove the rubber stopper or orange septa. You should never heat a closed system. Gently lower the flask into the boiling water. Heat for 10 minutes.
a. Lift the flask out of the boiling water using the clamp, then allow to cool to room temperature
b. Add 1 mL of distilled water to the mixture. Let it sit for 1 minute
4) Fill your large beaker with ice water and lower your flask into the ice bath
a. Add 40 mL of distilled water to the flask
b. Keep in the ice bath for 10 minutes.
5) Vacuum filter and weigh your product.
6) Place the solid in your 50 mL Erlenmyer flask
a. Add 10 mL of ethanol to the flask and dissolve the solid
b. Add 20 mL of distilled water
c. Heat on your hot plate until all remaining solid dissolves
7) Place in your ice bath and crystallize for at least 20 minutes.
a. Start your other experiment. Once completed, continue with the aspirin synthesis
8) Weigh your Hirsch funnel with a filter, record the weight
9) Vacuum filter your product. Be sure to pull air through the product for 5-10 minutes to dry the product as much as possible. Reweigh the filter funnel and filter with product, record the weight, determine the yield of the product.
10) Calculate a percent recovery (final mass/crude mass * 100) and a percent yield.
11) Measure the melting point range of your product when you are confident that it is completely dry.
12) Collect an IR spectrum of your pure product. Print copies for each lab partner. Draw the structure of aspirin on the spectrum and indicate the specific bond and functional group responsible for each of the important peaks.

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EXPERIMENTAL - INDIGO
Equipment
Stir bar, 50 mL beaker, Vacuum filtration apparatus, #10 microfiber cloth, Glass stirring rod
Chemicals
2-Nitrobenzaldehyde, 0.5g
Acetone, 5 mL
1 M NaOH, 12.5 mL
Sodium Dithionite = sodium hydrosulfite, 0.15g

Waste Disposal flammable, organic waste flammable, organic waste corrosive, aqueous basic waste flammable, organic waste

Safety Notes
1. 2-Nitrobenzaldehyde – flammable, toxic, and an irritant.
2. Acetone – highly flammable and irritating to the skin, eyes and mucous membranes.
3. Sodium Hydroxide – sodium hydroxide solution is extremely corrosive. If skin or eyes come into contact with the NaOH rinse with water for 15 minutes.
4. Sodium Hydrosulfite – flammable, toxic, hydroscopic, and an irritant. Can spontaneously ignite in moist air. Make sure to follow instructions exactly. Do not leave powder exposed to air.
5. Indigo – not hazardous but will stain skin and clothes, so be careful handling it.
Procedure
1) Combine the following in a 50 mL beaker set on a stir plate
a. A stir bar
b. 0.5 g of 2-Nitrobenzaldehyde
c. 5 mL of Acetone
d. 2.5 mL of 1 M NaOH added drop-wise
2) Stir for 10 minutes
3) Vacuum filter your product. IMPORTANT! The blue indigo solution must be poured onto the center of the (pre-wetted with water) filter paper while your vacuum aspirator is running. Do not let the blue solution come into contact with your Buchner funnel, or it will irreversibly color the funnel.
4) Dye with your Indigo
a. Add the following to a 50 mL beaker
i. 0.1 g of your product
Rayon!
ii. 0.15 g of Sodium Dithionite iii. Grind the two together with a glass stirring
Cotton!!
rod
Nylon!
iv. 10 mL of 1 M NaOH
b. Heat the mixture until the solution turns yellow
Dacron!
c. Add a piece of Multifiber Fabric 10 to the beaker
Orlon!
d. Rinse your piece of fabric with water and leave to dry, observe the color changes
Wool!
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Multifiber*Fabric*10!

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PRE-LAB INSTRUCTIONS
The following things need to be included in your lab notebook and completed before coming to your lab period:
Objective: include the main goals in words. molecules such as aspirin and indigo?

What is the advantage of being able to synthesize organic

Reaction: Draw out all of the reactions to be performed today. Show structures, not just names, of molecules. Mechanism: No mechanisms are necessary for this lab. You will learn these mechanisms in Chem 2320. If you are interested in seeing the mechanism please let me know.
Table of reagents and products: I have created an example of a table of reagents and products for a standard synthesis lab below. Notice that the starting material, reagents, and product are included along with the information required to eventually determine the limiting reagent, calculate a percent yield (MW and density) and to analyze the product (mp). Please create a similar table in your notebook so that you can record actual amounts used in grams or milliliters AND in moles.
Table of reagents and products - Synthesis of Aspirin
Salicylic acid

Acetic anhydride

Acetylsalicylic acid

MW (g/mol)

138.12

102.09

180.16

d (g/mL)

NA

1.080

NA

mp (oC)

158-161

NA

138-140

Amount used/obtained (g or mL)
Amount used/obtained (mol)

Table of reagents and products - Synthesis of Indigo
2-nitrobenzaldehyde

Sodium hydroxide

Acetone

Indigo

MW (g/mol)

151.12

1M

58.08

262.27

d (g/mL)

NA

NA

0.791

NA

mp (oC)

42

NA

NA

390-392

Amount used/obtained
(g or mL)
Amount used/obtained (mol)

Procedure: Reference the lab handout for details. Include a simple outline in your notebook.
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OH

HD O

O
CH3

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1) The!yellow!copy!of!your!notebook!pages!through!the!calculations!section!
2) Annotated!IR!spectra!of!aspirin!and!salicylic!acid!!
3) Typed!Conclusion!(2!pages!of!text,!double!spaced)!

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Include!the!reaction!used!to!synthesize!indigo!(show!structures).!
Why!is!leucoUindigo!more!waterUsoluble!than!indigo!itself?!!
What!are!the!dyeing!results!for!each!fiber?!Why!does!indigo!dye!each!fiber!to!a!different!extent?!Explain!based! on!the!structures!of!the!polymeric!fabrics!and!indigo!itself.! Early!on!there!was!a!serious!controversy!regarding!the!use!of!“natural”!versus!“synthetic”!indigo.!!Are!natural! and!synthetic!indigo!different?!!Is!it!safe!to!assume!that!any!product!that!is!“natural”!is!safer!than!the!synthetic! version!or!even!more!broadly!that!all!products!that!are!“allUnatural”!are!safe!to!use/consume?!!!

HC

The!following!items!are!due!one!week!after!you!perform!this!experiment:!

!

!

!
!
!

Indigo!

!

•

Print!a!copy!of!the!IR!of!salicylic!acid!available!on!canvas.!!Draw!the!molecule!directly!on!the!spectra.!!Then,! label!the!important!peaks!with!the!bond!and!functional*group*responsible!for!the!important!peaks.!!!!Attach!this! to!your!final!report.!
• Draw!the!structure!of!aspirin!directly!on!the!IR!spectra!of!the!aspirin!you!synthesized.!!Indicate!which!bond*and! functional*group!are!responsible!for!each!important!peak.!! • !In!your!conclusion*indicate*which*peaks*either*present*or*absent*in*the*product*mixture*IR*would*help*to* indicate* if* a)* the* starting* material* had* been* completely* consumed* and* b)* the* desired* product* had* been* synthesized.! ! Write a discussion of what was observed and learned from this experiment. The discussion should be typed, doublespaced, 12 font. Limit = 2 pages (limit applies to text only. This means that tables and structures, etc do not count towards limit). Incorporate at least the following ideas into your discussion: !
Aspirin!
! Include the reaction used to synthesize aspirin (draw structures).!
! Did!you!actually!isolate!acetylsalicylic!acid?!!What*evidence*do*you*have*to*support*your*claim?!!Be!sure!to! compare!your!observations/values!to!literature!values!and!provide!a!reference!for!the!reported!values.!!What! was!your!percent!recovery?!!Percent!yield?!!What!would!you!do!differently!next!experiment!to!improve!the! percent!recovery!or!percent!yield?!!How!pure!is!your!product?!How*do*you*know?**(Use*specific*data*to*support* your*claim).!!!!If!impure,!what!are!the!most!likely!impurities?!!Which!peaks!can!you!focus!on!in!the!IR!to! determine!whether!or!not!you!have!converted!actually*salicylic!acid!into!acetylsalicylic!acid?!!!! ! !Thinking!a!little!about!NMR…!Explain!why!protons!HA!and!HC!of!aspirin!are!found!at!higher!chemical!shift! values!than!protons!HB!and!HD.!!! HA O
!
HB

Post-lab Report:

Calculations! –! show! your! work! for! calculation! of! percent! yield! for! aspirin! and! indigo.! ! Be! sure! to! include!units.!!! Observations! –! record! EXACT! amounts! of! reagents! used! (use! table! similar! to! one! shown! above),! observations,! and! any! changes! you! have! made! to! the! written! procedure.! ! ! This* should* be* written* directly*in*your*notebook*as*you*complete*the*lab.*!! In$lab!Notebook:!