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

Introduction:

Most target compounds must be synthesized by multiple reaction steps. A successful synthetic organic chemist must learn to design such a synthetic sequence, and then refine it to maximize the yield of product. As an example, here is a scheme for the synthesis of 1-Bromo-3-Chloro-5-Iodobenzene from benzene in eight total steps.

We won’t do all of this, but over the next two labs, you will start with compound 7 and synthesize compound 9 in two separate reactions. These reactions demonstrate several aspects of synthetic reactivity you have learned or are learning in the lectures: electrophilic aromatic substitution, directing effects of substituents on substitution reactions (and how to manipulate the process), and the use of diazonium salts in synthesis.  These experiments also provide practice in determination of structures from spectroscopic data (IR, NMR, and GC/MS), solvent extraction, filtration, and the use of mixed-solvent recrystallization. This reaction series also demonstrates the challenge of getting a high overall yield from a multi-step synthesis.

Part 1: Synthesis of 4-Bromo-2-Chloro-6-Iodoaniline

Pre-lab Work:

1. Reading Assignment: 

• Review Electrophilic Aromatic Substitution (2nd ed. Hornback, Chapter 17.)
• Review Mixed Solvent Recrystallization in Section 15.3

    2.    Fill in the quantities in the table of Physical Constants for Lab 5 below.

Ref. -- Handbook of Chemistry and Physics; CRC Press, 87th ed.

Safety:

Experimental:

·        Dissolve 0.006 mole of 4-bromo-2-chloroaniline in 20 mL of glacial acetic acid, and add approximately 5 mL of water to the mixture.

·        Add 0.0075 moles of iodine monochloride solution to the reaction mixture over a period of 8 minutes.  

·        Heat the resulting dark mixture to approximately 90°C in a beaker of water on a hot plate, and add just enough saturated sodium bisulfite solution to remove the dark purple color and turn the solution a mustard-yellow color (i.e.-not purple). What reaction is taking place when you add the sodium bisulfite solution?

·        Dilute the reaction mixture with enough water such that 10 mL is the total volume of bisulfite solution and added water.  When the reaction mixture is cooled in an ice bath, the product will precipitate out. 

·        Collect the solid by vacuum filtration, washing it with a sparing amount of cold 33% acetic acid followed by a small amount of cold water.  Leave the material on the filter to dry for at least 10 minutes, then mass it on a balance.

·        All of the product obtained in this step must be recrystallized using a solvent pair recrystallization technique in order to obtain good results in the final synthetic step.  To recrystallize, mix the product with the pre-measured amount of boiling glacial acetic acid (20 mL per gram of product) and stir to dissolve.  Make sure all the solid has dissolved before adding water.  Once the solid is dissolved, add the pre-measured amount of boiling water (5 mL per gram of product).  

·        Cool the solution slowly to room temperature and then in an ice bath.  Long crystalline needles will be formed.  Filter and wash the crystals with a few mL of cold water and dry.  Obtain the mass of your dried product.

• Analyze your product based on the instructions supplied by your instructor.  For NMRs, please use deuterated-chloroform (CDCl3). Please follow the procedure given earlier in the lab manual for preparing your sample (i.e.-use a test tube to prepare your solution for the NMR instrument.) 

Save your product. You will use it for Part 2 of the Synthesis of 1-Bromo-3-Chloro-5-Iodobenzene.

Waste Disposal: 

• The filtrates and rinsings from this lab should be discarded in the aqueous waste bottle, which is labeled water, acetic acid, sodium bisulfite, and iodine monochloride.
• 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 should be rinsed with acetone into the organic flammable waste bottle, allowed to dry, and disposed of with other solid waste.

Results: 

1. Report observations about the reaction and products. Calculate percent yield and show your calculations.
2. Did you make your desired product?  Please justify your answer with lab data (data you obtained/supplied to you.) Explain the pattern seen in the parent ion region (aka-"M+" region) of the mass spectrum.

Questions to ponder…

1. During your experiment, why did you add the ICl solution slowly and why was it important to heat your reaction, but not boil it as you were adding the saturated sodium bisulfite solution?
2. Using ChemDraw, show the mechanism for the synthesis you attempted in this lab.
3. Using ChemDraw, show the balanced redox reaction between sodium bisulfite and iodine to create iodide and sulfuric acid.