A Two-Step Synthesis of 1-Bromo-3-Chloro-5-Iodobenzene

Part 2: Synthesis of 1-Bromo-3-chloro-5-iodobenzene

Of particular interest will be our today’s lab where you will create a diazonium ion.  The diazonium ion acts as an excellent leaving group due to the loss of nitrogen gas (N2) as the product of this reaction.  As usual in organic chemistry, there are several different reagents that can be used to produce the diazonium ion.  Your textbook uses sodium nitrite and hydrochloric acid to produce the nitrosonium ion (NO+) which reacts with the amine, as can be seen in the following reaction mechanism:

Yet, in our lab, we will use isoamyl nitrite in DMF to produce our diazonium ion as shown in the possible reaction mechanism below:

The rational behind using the above aprotic diazotization reaction over the textbook synthesis was due to several procedural benefits that allowed us to perform the reaction in a shorter time period while not sacrificing any product yield.  In the end, the creation of the diazonium ion is the key and not only will help us remove our strongly o,p-directing amine, but could be used to produce several different functional groups, as seen in the image below:

http://chemwiki.ucdavis.edu/@api/deki/files/1482/diazoprd.gif

Pre-lab Work:

1. Reading Assignment: 
   Review Diazonium Ions (2nd ed. Hornback, Sec. 17.10.)
2.  Complete the table below. Use the mass of 4-Bromo-2-Chloro-6-Iodo-aniline you obtained last week, or if you made less than 1 g use 1 g in the table, and we will provide the necessary amount to bring your total to 1 gram. 

Ref. -- Handbook of Chemistry and Physics; CRC Press, 87th ed. and Roberts, Gilbert at al., 3rd ed. Modern Experimental Organic Chemistry.

Safety

• 4-Bromo-2-chloro-6-iodoaniline (The following information is for 2,4,6-tribromoaniline and is only used as a comparison for a similar compound.)  is highly toxic if absorbed through the skin or inhaled and can cause irritation to eyes and skin.  Avoid contact and flush exposed area with water.
• Isoamyl Nitrite in DMF is a skin and eye irritant.  Flush exposed area with water.
• N,N-Dimethylforamide (DMF) is harmful by inhalation, ingestion or skin contact.  Avoid contact and flush exposed area with water. 
• 3M HCl can cause severe irritation and burns.  Avoid contact and flush exposed area with water. 
• Diethyl ether is extremely flammable.
• Methanol is an irritant and toxic by inhalation, ingestion or skin absorption

Experimental: 

NOTE: The procedure given below is written assuming you have 1.0 grams of starting material.  If you have more than 1.0 grams of starting material, please scale the following procedure to suit the amount of material you have for this reaction.  If you have less than 1.0 grams, than you will be given enough starting material to allow you to start the reaction with at least 1.0 grams of 4-bromo-2-chloro-6-iodoaniline.

·         Set up a small reflux apparatus using a 100-mL round bottom flask.

·         Add 6 mL of 0.75M isoamyl nitrite in DMF solution to the flask. Move the reflux apparatus to a water bath. Heat the water bath to approx. 70°C at a medium rate. Turn off the heat. Remove the hot plate to the bench.

·      While the solution is warming, dissolve 1.0 grams of 2-chloro-4-bromo-6-iodoaniline in 5 mL of DMF.

·       Add this solution dropwise through the reflux condenser using a 9-in. disposable glass Pasteur pipet.  Your reaction will not boil, but should be kept warm in the water bath. Observe closely and note the formation of small gas bubbles at the site of addition

·         After all the solution has been added to the warm flask, let the mixture cool to room temperature and then carefully transfer its contents to a 125-mL Erlenmeyer flask.

·         Add 30-mL of 3M HCl to the mixture and swirl gently. Transfer the mixture to a 125-mL separatory funnel and extract your product from the aqueous layer with 2 washes of the aqueous layer using approximately 20-mL of diethyl ether each to obtain a total volume of approximately 40-mL.  Vent often while shaking…diethyl ether is extremely volatile!  Collect the aqueous and organic layers.  Combine the two organic (diethyl ether) extracts and wash that with approximately 20-mL of 3M HCl.

·         Dry the ether extract with  magnesium sulfate.   Evaporate the diethyl ether to obtain your crude organic product.  

·         Recrystallize your crude product using approximately 5-10 mL of hot methanol per gram of crude product in a 100-mL Erlenmeyer flask. After drying, obtain the mass of your pure product.

·         Your instructor will provide directions on how to analyze your product.  Please use CDCl3 to make up your NMR sample.

Waste Disposal:

• The filtrates and washes from this lab should be discarded in the aqueous waste bottle, which is labeled water, DMF, hydrochloric acid, and organics n.o.s. 
• Any excess diethyl ether, pure DMF, and methanol should be disposed of in the organic flammable waste bottle.
• Rinse any glassware containing these wastes with water from the wash bottles in the waste hood and add the water wash to the aqueous waste container.  Perform a final rinse of all glassware with acetone and place this waste in the organic flammable waste bottle.
• Used plastic pipets should be emptied and disposed of with other solid waste.
• Used filter paper, magnesium sulfate, and phase paper should be rinsed with acetone into the organic flammable waste bottle, allowed to dry, and disposed of with other solid waste.

Results:

1. Note observations about the reaction and purification.
2. Did you make your desired product?  Please justify your answer with your lab data.  
3. Calculate the % yield for this reaction and your overall 2-step % yield.  [Overall yield is calculated by multiplying the decimal form of the yield obtained in all the steps.  For example, if the yield of three consecutive steps was 50%, 25%, and 50% respectively, the overall yield for the process would be: (0.50 x 0.25 x 0.50) x 100 = 6.25%.]  

Questions to ponder…

1. During your experiment, your reaction took place in a reflux apparatus over a steam bath.  If you looked closely during the addition of your aniline/DMF solution you should have seen small bubbles being generated.  Your solution was not hot enough to boil the solution, so what compound was being released as gas bubbles?
2. During your experiment, you added 3MHCl to your reaction.  Please discuss the chemistry taking place at this point of your experiment.
3. Discuss the synthetic approach for the synthesis of 1-bromo-3-chloro-5-iodobenzene starting with benzene.  (Explain why each step of the synthesis was performed in this order.  Could the synthesis be done with the same chemicals, yet performed in a different order?)
4. If you could choose only one method of spectroscopic analysis (H NMR, C NMR, FTIR, or GC/MS) to analyze and confirm the products of this 2-step synthesis, which method would you choose?  Give reasons for your choice and suggest any reasons, if applicable, why one method might or might not give you enough information to confirm your products.