Kathleen Armstrong
Foothill College Chemistry

Multi-step synthesis of bromoaniline

This three step reaction sequence encorporates a number of features important to our study of synthetic organic chemistry. In this multi-step synthesis, each subsequent step relies on the success of the previous step, and each will require skill with a number of Organic Chemistry laboratory techniques.

The first step involves the addition of a protecting group to the amino substituent of aniline (phenylamine). Without protection, aniline is too reactive and our desired product will not form. This sequence involves protection at one functional group (the amino group), reaction at another (substitution of Br for H on the aromatic ring) and finally deprotection of the amino group. The amino group in Aniline is highly reactive because it can be easily oxidized and because it is so electron rich that it tends to undergo polysubstitution in Electrophilic Aromatic Substitution (EAS) reactions. In order to limit its reactivity to mono-substitution via EAS, the amino group is acetylated to form acetanilide. Bromination of acetanilide in step two produces a mixture of ortho and para product (via the resonance stabilized carbocation intermediates). The para product is dominant and less soluble in the solvent than is the ortho. The para is therefore easily isolated and subjected to hydrolysis of the acetyl group in the final step of the synthesis. All products can be easily characterized by IR and NMR spectroscopy.

This reaction sequence illustrates the importance of protecting group chemistry and highlights the chemistry of electrophilic aromatic substitution.

multistep reaction sequence

 

Step One:
Acetylation of Aniline

acetylation of aniline

This step is done on a miniscale and will require careful planning in order to be accomplished in the time alloted.

In order to prepare for this lab, you will need to review the procedure given below and review Mohrig's "Techniques" text on Reflux and Infrared Spectroscopy.

Once you have read the text, you will need to prepare your notebook with the following:

  1. Purpose

  2. Net Reaction

  3. Mechanism

  4. Table of Reactants/ Products/ Solvents
    Include ALL solvents (density, bp and handling info), and any reactants or products used in determining the Theoretical Yield

  5. Theoretical Yield Calculation in grams

  6. Procedure
    The procedure for this experiment is not in your textbook, but rather is given in this .pdf document . Read this carefully and then write an outline of what you will do in your notebook.
    Leave room to the right of the procedure for notes/ observations/ changes on the day of the experiment.

During the lab:

Remember to date every entry, record all weights, observations, corrections and melting points IN PEN IN YOUR NOTEBOOK. You will be marked off if I catch you recording data on scratch paper, or if you do not have your notebook with you when you take a measurement.

Determine the melting point and the yield of dry acetanilide.

Following Lab:
Calculate the percent yield of acetanilide from the original quantity of nitrobenzene used in step one. Take a melting point of your product once it is dry.

 

Step Two:
Bromination of Acetanilide

Electrophilic Aromatic Substitution of Acetanilide

Bromination of Acetanilide can be effected by generating molecular bromine insitu with potassium bromate in Hydrobromic Acid solution. The acetanilide functional group possesses unbonded electrons and can stabilize the carbocation intermediate through resonance. For this reason, the group is Activating (reacts faster than benzene) and ortho/para directing (so that the resonance stabilization can take place). Acetanilide is sufficiently electron rich that the usual Iron tribromide catalyst is not needed under these strongly acidic conditions (recall that carbocations are stabilized in acidic media).

The bromoacetanilide product is a combination of the ortho- and para- isomers, but the para- isomer is less soluble in this aqueous solvent and will preferentially crystallize out of solution. We will recrystallize it from ethanol to isolate pure para-bromoacetanilide. We will save some product for a MP and IR spectrum and hydrolyze the rest in step four.

In order to prepare for this lab, you will need to review the procedure given in your experiment text under "Experiment 20" and review Mohrig's "Techniques" text on Reflux and Infrared Spectroscopy.

Once you have read the text, you will need to prepare your notebook with the following:

  1. Purpose

  2. Net Reaction

  3. Mechanism

  4. Table of Reactants/ Products/ Solvents
    Include ALL solvents (density, bp and handling info), and any reactants or products used in determining the Theoretical Yield

  5. Theoretical Yield Calculation in grams

  6. Procedure (Microscale)
    Read the procedure given in your laboratory textbook (Experiment 20) carefully and then write an outline of what you will do in your notebook.
    Leave room to the right of the procedure for notes/ observations/ changes on the day of the experiment.

During the lab:
Potassium Bromate is a cancer suspect agent and highly flammable. Wear gloves and do not handle or dispose of the potassium bromate with paper. Discard the weighing paper and any residual potassium bromate in the specially labelled container in the waste hood. Bromine is generated in solution and is highly toxic. Do not leave the solution open in the lab, but rather keep the trap on at all times unless you are working in the fume hood. It is very important that your solution be stirred to facilitate contact between the reagents in this aqueous solvent.
Remember to date every entry, record all weights, observations, corrections and melting points IN PEN IN YOUR NOTEBOOK. You will be marked off if I catch you recording data on scratch paper, or if you do not have your notebook with you when you take a measurement.

Determine the melting point and the yield of dry bromoacetanilide. Record an NMR spectrum in acetone-d6 as solvent.

Following Lab:
Complete the summary sheet (.doc) and attach to the top of your data and 1H NMR specctrum.



Step Three:
Hydrolysis of Acetamide

The procedure below is written for 0.35 g of the bromoacetanilide. If you have more or less than this amount, please adjust the reactant and solvent quantities proportionately.

Into a 10 mL round-bottom flask fitted with a reflux water condenser and a magnetic stirrer, add .35 g of 4-bromo-acetanilide, 0.7 mL of 95% ethanol, and .5 mL of concentrated HCl. Heat the solution, with stirring, to a gentle boil and continue refluxing for at least 1 hour. The solid will dissolve as it is heated, and then a white precipitate will form. Heat 3 mL of water on a hot plate. Pour the hot water into the reaction mixture and swirl the flask to redissolve the solid. Pour the reaction mixture onto 5 g of ice. While stirring,, add 0.40 mL of 50% sodium hydroxide solution. Use pH paper to check the pH of the solution. if the pH is stilll acidic, add a little more NaOH until the stirred solution is baic to litmus paper. Collect the crude product by suction filtration, washing well with cold water. The product may be recrystallized from hexanes. Let dry in air before recording the weight and melting point.

Obtain both IR and NMR spectra.


Post Lab Study Questions:

  1. Use the method of half-reactions to show a balanced chemical equation for the reduction of nitrobenzene to aniline assuming that tin is oxidized to SnO2.
  2. Why is sodium acetate added to the reaction mixture in the acetylation of aniline with acetic anhydride?
  3. Explain why acetanilide is an ortho-/para- director. Predict the product of di-bromination of bromoacetanilide. Is this reaction slower or faster than the formation of mono-bromoacetanilide? Explain.

 

 


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©Kathleen Armstrong April, 2011