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EXP-10
SYNTHESIS OF p-BROMOANILINE
CHEM 233L
Introduction:
In this experiment, p-bromoaniline was synthesized in three steps starting from aniline. Since the amino group of aniline is a strong activator of aromatic ring, direct bromination is impractical (equation 1). In order to make a desired product, amino group needed to be protected as the acetamide which also maintained ortho and para position but slowed down the rate of reaction (equation 2). Slow reaction rate would increase the possibility of obtaining the para-position product (equation 3). The acetamide can be hydrolyzed back to the amine (equation 4). This strategy of protection and deprotection is a very important tool in organic chemistry, especially in multi-step synthesis.
Equation 1:
NH
2
NH
2
Br Br
Br
2
Equation 2:
Aniline
NH
2
O O
O
Acetic anhydride
Br plus mono-and-di-derivative
O
HN
Acetanilide
Equation 3:
Aniline
O
HN
Br
2
HN
O
Equation 4:
Acetanilide
O
HN
Br
Bromoacetanilide
NH
2
Acid hydrolysis
Br
Bromoacetanilide
Br
4-bromoaniline

Table of Physical data:
Compound Molecular
Weigh (g)
NH
2
93.128
Amount Density
(g/ml)
Moles Melting point m.p. o C
2.0 ml 1.021 0.0219 -6.2
Boiling point b.p o C
184
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Aniline
HCl concentration
Water
Cl -
NH
3
+
36.460
18.015
129.588
Anilinium chloride
O O 102.089
O
Acetic anhydride
O
Na +
O -
Sodium acetate
O
82.034
135.165
HN
2.0 ml
2.56 ml
0.909
1.221
1.08
3.3147 g 1.45
0.6718 g 1.219
0.0498
50 ml 0.909 ---
0.0270
0.0404
-114.24
0
198
-73.1
58
0.00197 114.3
-85.06
100
245
139
304
Acetanilide
Acetanilide
Safety notes :

Bromine is very corrosive. Wear gloves when using it.
 p-Bromoaniline is harmful if inhaled or absorbed through the skin

Aniline is highly toxic. It is possible mutagen, sensitizer, and readily absorbed through the skin.

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Procedure:
EXP-10A:
1.
Dilute 2.0 ml of concentration HCl in 50 ml of water in a 125 ml flask, then add
2.05g (2.0 ml) of aniline.
2.
Stir the mixture until the aniline completely dissolves. HCl and aniline reacts forming anilinum chloride. (A reaction for this step was included in your report).
3.
Add 2.77g (2.56 ml) of acetic anhydride, stir until it is dissolves and immediately pour a solution of 3.3g of sodium acetate in 10 ml of water into the flask.
4.
After complete addition, stir vigorously for 5 minutes, then cool in ice.
Crystallization should occur. When no more crystals seem to form (5—10 minutes), vacuum filter the acetanilide, wash the crystals with small volumes of cold water and air dry for 5 minutes.
5.
Pure acetanilide is usually obtained as white flakes. Recrystallize the obtained acetanilide from a minimum of hot water. Use 10 ml of water to start and increase the amount of water depending on the amount of acetanilide.
6.
If the initial crystals were not white, add 0.5g of decolorizing charcoal to the product in water and then heat to gently boiling.
7.
Remove the charcoal by hot gravity filtration ,using two pieces of fluted filter paper. To avoid contaminating the filtrate with charcoal, do not overflow the filter funnel.
8.
After recrystallization, wash the crystals again with small volumes of cold water.
9.
Dry the product, obtain an IR and melting point.
10.
The typical yield is 2.0 g. Submit 100mg of your product and the rest for the next experiment.
Table of physical data EXP-10B:
Compound Molecular
Weigh (g)
Amount Density
(g/ml)
O 135.165 ---- 1.219
Moles
----
Melting point m.p.
o C
114.3
Boiling point b.p.
o C
304
HN
Acetanilide
Bromine
Acetic acid
Solvent
O
HN
159.808
60.052
214.061
1.5 ml
2.0 ml
3.119
1.049
0.0293 -7.2
0.0349 16.6
165-166
58.7
117.9
Br p-Bracetanilide

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HN
O 214.061
Br m-Bracetanilide
O 214.061
HN
Br o-Bracetanilide
NaHSO
3
Reducing agent
Ethanol
Recystallized solvent
104.055 Reduced
46.068 bromine
1.48
2.0 ml 0.789
---
0.0342 -114.1 78.3
Procedure:
EXP-10B:
1.
Place 1.0 g of acetanilide in a 50 ml Erlenmeyer flask.
2.
Add 4.0 ml of acetic acid and swirl until the solid dissolves.
3.
Place a magnetic stirring bar in the flask and place the flask on a hot plate and clamp.
4.
In the hood, obtain 2.5 ml of 1:4 of 4.1 M bromine/ acetic acid.
5.
In the hood, add the bromine drop-wise using a disposable Pasteur pipet over a period of 5 minutes. The flask was covered with a small beaker and stir the reaction mixture for another 15 minutes to complete the reaction.
6.
In the mean time, clean the used pipet and graduated cylinder with 2 ml of aqueous
NaHSO
3
. Bromine will be destroyed or its color will change from red to clear by sodium bisulfide.
7.
In the hood, pour the reaction mixture into a 150 ml beaker containing 30 ml of water. Rinse the reaction flask with additional 10 ml of water. A precipitate should form.
8.
Stir the precipitate with a glass rod to break up any chunks. If the solution still has an orange color from excess bromine, add aq. NaHSO
3
(sodium bisulfite) drop wise until the color is discharged.
9.
Collect the crude product by vacuum filtration and wash the solid 4 times with 10 ml of cold water (mix equal parts of ice and water).
10.
Transfer the crude solid into a 125 ml Erlenmeyer flask.
11.
Recrystallize the major product from a minimum amount of hot ethanol. It is recommended to try to dissolve the solid in approximately 5 ml of boiling ethanol.

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Additional ethanol was added if necessary. Keep track of the amount of solvent used.
12.
While heating, add 1ml of water for every 2ml of ethanol used (or half the volume).
13.
Allow the solution to cool down at room temperature. Crystals should appear. Chill the crystallized material for 5 minutes and then isolate by vacuum filtration. Rinse your product with cold water.
14.
Dry the crystals overnight.
15.
Calculate the % yield. Obtain an IR and a melting point. Save 100 mg and submit with other product. The rest is used for the next step.
Table of physical data:
EXP-10C:
Compound MW (g) Amount Density
(g/ml)
O 214.061 0.6525 ---
Moles
0.00305 m.p. o C b.p.
165-166 o C
HN
Br p-Br-acetanilide
O
HO
S
OH
O
Conc H
2
SO
4
6 M NaOH
NH
2
98.073 5ml 1.84
39.997 25 ml 2.13
172.024 0.3782 g 1.5
0.0938 3
1.33
0.00220
318
66.4
280
1390
---
Br p-bromoaniline
H 84.932 30 ml 2.165 -96.7 39.8
H
Cl
CH
2
Cl
2
NaCl
Ethanol
58.443 20 ml
46.068 ---
0.789
0.789
---
---
801
-114.1
1413
78.3
Procedure:
EXP-10C:
1.
Transfer 1.0g of p-bromo-acetanilide into a 100 ml round-bottomed flask. Add 10 ml of water into the flask.
2.
Chill the mixture and add 10 ml of concentrated sulfuric acid carefully and slowly.

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3.
Heat the mixture to reflux for 1 hour.
4.
Initially the p-bromoacetanilide will be insoluble but as the reaction progresses it will completely dissolve.
5.
Stop the reaction and wait 5-10 minutes for the mixture to cool off.
6.
Analyze the crude reaction mixture by TLC by using 10 ml of Hex/EtAc 8:2 as solvent.
7.
Dissolve the samples in EtOAc (ethyl acetate)
8.
Spot the p-bromoactanilide, the crude mixture and a co-spot and visualize by
U.V. Estimate the extent of the reaction. The product should stay at the origin.
9.
Is there any starting material left? Is the reaction complete? If the reaction is not complete, continue the refux for another 30 minutes to an hour.
10.
Upon completion, cool the reaction flask and pour the contents into 20 mL of iced-cold water.
11.
Neutralize the acidic solution with 10 M NaOH. Theoretically, it should require
18 ml of 10 M NaOH to neutralize the sulfuric acid present.
12.
Add the aq NaOH solution portion-wise with the help of a Pasteur pipette.
13.
When half of the theoretical volume has been added to check the pH. Add enough
NaOH to bring the pH to 8. If a different concentration of NaOH is used, the required theoretical volume is calculated.
14.
Transfer the neutralized solution to a separatory funnel and extract the free amine with 3 X 10 ml of CH
2
Cl
2.
15.
Back extract the combined organic layer with 20 ml of water and 20 ml of saturated sodium chloride (NaCl).
16.
Dry the CH
2
Cl
2
over anhydride Na
2
SO
4
. Remove the drying agent by gravity filtration and evaporate the CH
2
Cl
2
in the hood over low heat.
17.
Remove the solvent, as the oily residue begins to crystallize.
18.
Allow the crystals to dry overnight. Check the purity of the product by IR.
19.
Check the melting point of final product and calculate the % yield.
Reference: