EXPERIMENT C: IODINATION OF SALICYLAMIDE WITH NAI/BLEACH PDF

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lab assignment for chemistry lab done in CH203. Chemistry lab EXPERIMENT C: IODINATION OF SALICYLAMIDE WITH NAI/BLEACH...

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EXPERIMENT C: IODINATION OF SALICYLAMIDE WITH NAI/BLEACH LAB LEARNING OBJECTIVES 1. Reinforce mechanism of and substituent effects in electrophilic aromatic substitution (EAS). 2. Predict the major product of an EAS reaction by considering effects of substituents already present on the ring. 3. Use IR spectroscopy to confirm the substitution pattern in a benzene ring. 4. Carry out, with confidence and efficiency, a synthetic protocol including reaction set up, product isolation and purification. 5. Perform, with confidence and efficiency, the following laboratory techniques: (i) accurate measurement and safe handling of starting materials, reagents, solvents; (ii) suction filtration and (iii) recrystallization. 6. Evaluate the greenness of a chemical reaction using green chemistry metrics. PRE-LAB ASSIGNMENT (No lates accepted. Flow charts must be typed and clearly visible) In Experiment C, you will carry out an electrophilic aromatic substitution (EAS) reaction on salicylamide, a component of some analgesics. The product will be isolated and purified by recrystallization. 1.

Predict the major monoiodinated product of this reaction. Explain why your suggested major product would be formed in higher yield than any of the other possible monoiodinated products.

2.

For each of the following, provide the structure of the major monoiodinated product expected following treatment with the conditions used in this experiment. (a)

O

(b) H

(c) CH 3

C H 3CO

3.

N

(d)

H 2N

Fill in the blanks in the following table (and insert a version of this table into your lab notebook so you can calculate your percentage yield in your lab notebook before leaving). Show your calculation to determine mass of NaOCl and theoretical yield. MW (g/mol) Salicylamide NaI NaOCl absolute ethanol expected product

Density (g/mL) n/a n/a

n/a

Amount used (in g or mL)

*

#mmol

#equiv

n/a n/a * * * theoretical, based on limiting reagent

4. What is a teratogen? Which of the chemical(s) you will use in this experiment have teratogenic effects been observed in toxicity studies? Look up and reference the SDSs to answer this question. SDSs are expected to come from one of the following sources: Sigma-Aldrich, Fluka, Acros, Alfa-Aesar. 5. Why is NaI used to react with NaOCl instead of I2? 6. Why is sodium thiosulfate used in this experiment? 7. The exact structure of the active “I+” species in this experiment is not known. What are two possibilities for the chemical formula of the active “I+” species? 8. Why must this experiment be performed at an ice bath temperature? What might the major product be if the reaction was performed at a higher temperature? Why should you be careful not to leave your reaction flask in the ice bath for more than 10 minutes? 9. This experiment uses absolute ethanol and 95% ethanol. Describe the chemical difference between the two and how each is used in this experiment. Look up the cost of each one. Why is absolute ethanol used in Part A and 95% ethanol used in Part B and C? (This is a two-part answer). 10. Provide one suggestion that would make this experiment greener with reference to GCP#s, be specific with an actual, applicable and practical suggestion. 11. Calculate the reaction mass efficiency for the reaction assuming the mass obtained of recrystallized product is 0.38g 12. Calculate the atom economy for the reaction. 13. If your percentage yield of recrystallized product was only 20%, what can you do to increase the yield of your recrystallized product once the experiment is already completed (ie you can’t just say “start over and lose ”? less 14. When is a TRAP normally required in vacuum filtration? Why might it be useful in Part B in this experiment? 15. Create a flow chart outlining the steps and separations followed in this experiment. Be specific in your terminology. Include your own academic integrity statement in this question. THEORY

As you have learned very recently in CH203, benzene is electron-rich, i.e., nucleophilic, yet it does not undergo electrophilic addition reactions typical of alkenes because these reactions would destroy the aromaticity of the ring, which provides benzene with unusually high stability. For this reason, benzene and other aromatics react via electrophilic aromatic substitution, in which the incoming electrophile replaces a hydrogen on the ring. Although aromaticity is destroyed in the first step of this reaction, it is restored in the second step such that, overall, aromaticity is maintained. +

H

E H

H H

H H

-

H

Y slow ar omati city dest royed

H

H

E H

H

H

fast

Y

+ H-Y

ar omati city r estored

H H

E

H

H H

A variety of electrophiles (E +-Y  -) will react with benzene, and derivatives Br Br of benzene, to yield substitution products. Halogenation of benzene rings O HO is an important reaction HO O OH CH3 because some Br O O H3C O Br Br Cl halogenated aromatics O O NH3 HO PBDE have important uses, e.g., Cl HO OH O O pentabromodiphenyl ether (PBDE; flame retardant) O H H H N N N N O and Vancomycin (naturally occurring antibiotic). N N CH3 H H O H H H H H O However, halogens are not very reactive toward O CH 3 HN HO2C benzene rings,1 and for this reason, they typically must H2N CH3 H be activated in some way to make them more OH Vancomycin OH HO electrophilic. For Cl2 and Br2, this is accomplished through coordination to a Lewis acid, FeCl3 or FeBr3, which polarizes the halogen and makes it more reactive. Iodine (I2) usually requires oxidation to I+, or a species that acts like I+, before it will react with a benzene ring. In this experiment, you will use EAS to iodinate salicylamide, a component of some analgesics. When salicylamide is monoiodinated, four different products may be formed. You will be asked to predict the major product of this reaction and explain how your prediction was made. OH O OH

OH O NH2

O

NaI, NaOCl NH 2

EtOH

I

NH2 OH

O

I

NH2

I

II

OH O

I III

I

NH2 IV

possible pr oducts of monoiodi nat ion of sali cylami de

UNDERSTANDING THE EXPERIMENT Fluorine is an exception. It is too reactive and usually does not allow for isolation of monofluorinated products. 1

The “I+” electrophile that is required to iodinate a benzene ring is often generated by the oxidation of I2 with various oxidizing agents (e.g., hydrogen peroxide or a copper salt like CuCl2). In this experiment, “I+” (possibly ICl or IOCH2CH3) is generated by the oxidation of NaI with sodium hypochlorite, NaOCl, a.k.a, common household bleach. Use of NaI is preferred to use of I2 which is volatile and toxic by inhalation. Phenols are very reactive toward EAS and so the reaction mixture must be cooled in an ice bath prior to the addition of NaOCl to slow down the reaction and increase the selectivity for the monoiodinated product. Despite cooling, the reaction is still quite fast as indicated by the quick color changes observed upon addition of NaOCl. Following complete reaction, sodium thiosulfate is added to react with or “quench” any unreacted “I+” electrophiles, reducing them back to NaI. Because this reaction is done in a basic medium in which the phenol would be deprotonated, the reaction mixture must be acidified prior to product isolation. INSTRUCTIONS HAZARDS: Salicylamide, sodium iodide and sodium thiosulfate are irritants. Sodium hypochlorite and hydrochloric acid are irritants and corrosive. Always wear gloves and appropriate eye protection when handling these compounds. Ethanol is flammable NO OPEN FLAMES. A. SETTING UP THE EXPERIMENT (REMEMBER TO HAVE YOUR REACTION TABLE AND OVERALL REACTION DRAWN AT THE TOP OF YOUR LAB NOTEBOOK ) 1.

Mass out 0.25 g salicylamide on a top loading balance and transfer it to a dry 25 mL Erlenmeyer flask. Add 5 mL absolute ethanol and dissolve the salicylamide by swirling the flask. You can warm the flask with your hands to help dissolve the salicylamide.

2.

Mass out 0.30 g sodium iodide and add this to your solution of salicylamide. Swirl the flask to dissolve.

3.

Once everything is dissolved in the ethanol, CLAMP your flask and cool your mixture to 0 °C in an ice bath for 5-7 minutes. Do not leave the flask in the ice bath for more than 10 minutes as some of the dissolved reagents may begin to precipitate out. If this happens, warm up the flask with your hands.

4.

Remove the flask from the ice bath and in the fume hood add 3.4 mL 4.25% (w/v) NaOCl (ultra-strength bleach) to the solution. Swirl the reaction mixture. There should be a colour change from colourless → dark red-brown → light yellow. Swirl until the light yellow color is observed, which should take up to ~10 minutes. You may also note a greenish tinge at this point. That is acceptable.

5.

Let the flask sit on the lab bench undisturbed for an additional 10 minutes.

B. ISOLATION OF CRUDE PRODUCT 1.

Add 2.5 mL 10% sodium thiosulfate solution and swirl to mix thoroughly.

2.

In the fume hood, add 10% HCl solution dropwise, keeping pipet upright, swirling the flask after every 2-3 drops, until the product begins to precipitate.

3.

Once precipitate is observed, continue adding 10% HCl dropwise, monitoring the pH closely using pH paper (or litmus paper), until the mixture becomes acidic. (To correctly test pH, take out a drop of solution using a Pasteur pipet or glass stirring rod and place on the end of the pH paper that you have not had contact with).

4.

Set up a vacuum filtration apparatus using a Hirsch funnel with a TRAP (CLAMP FLASK FIRST), while waiting for crystal size to increase for at least 5 minutes in an ICE BATH. (Remember to clamp your sample in the ice bath to prevent spillage and loss).

5.

Subject the reaction mixture to vacuum to collect the crude product. Filter slowly. If needed, rinse the original flask with 1-3mL of 95% ethanol to obtain maximum amount of crude product.

6.

Allow the crude product to sit under vacuum for 5 minutes to dry (If you aren’t holding down the edges of the Hirsch funnel, you aren’t drying anything).

7.

Record the mass of a dry 100 mL beaker then transfer your crude product to it. Reweigh to determine the mass of your crude product.

C. RECRYSTALLIZATION OF CRUDE PRODUCT 1.

Set up a hot water bath using a recrystallizing dish and hot tap water. Set hot plate temperature to maximum until water bath reaches ~85OC.

2.

Add 5 mL 95% ethanol and a stir bar to the beaker containing the crude product. Clamp the beaker in the hot water bath. Heat the solution with stirring until all solid has dissolved. Carefully monitor the reaction as the ethanol can begin boiling vigorously and start bumping.

3.

Once the solid is dissolved, remove the beaker from the hot water bath and allow it to cool to room temperature without disturbing the beaker. Carefully clamp the beaker in an ice bath to further precipitate crystals (If your crystals fall over into your ice bath, you will have to start over!). You may slowly, with intent, scratch the bottom of the beaker with a glass stir rod to

promote the formation of crystals if none have started to form after 10 minutes in an ice bath. Wait 20 minutes in the ice bath for crystals to form. 4.

Set up vacuum filtration apparatus with Hirsch funnel . Decide which chemical to wet the filter paper and filter crystals. Rinse out beaker with 95% ethanol if required. Collect your recrystallized product.

5.

Allow your pure product to dry under vacuum for 5 min. Determine the mass of your recrystallized product.

6.

Calculate your actual percentage yield of both crude and pure product in your lab notebook.

7.

Dispose of all waste materials in the appropriate containers and clean all glassware thoroughly, placing in the bin as required.

8.

Get your lab notebook checked for pass/fail and your bin checked for SPT marks by your IA or LC before leaving....