Six-Step Synthesis: Aniline to 1-Bromo-3-chloro-5-iodobenzene

I. Pre-Lab Report

A. Introduction

The purpose of this experiment is to convert aniline to 1-bromo-3-chloro-5-iodobenzene via a six step synthesis reaction that for the most part involves electrophillic aromatic substitution. First, aniline will be converted to acetanilide using acetic anhydride. Next, bromine will be added to acetanilide in a solution of acetic acid to yield 4-bromoacetanilide. Then, chlorine will be introduced to 4-bromoacetanilide again in a solution of acetic acid to produce 4-bromo-2-chlroracetanilide. An acid-catalyzed hydrolysis will then take place to convert 4-bromo-2-chlroracetanilide to 4-bromo-2-chlroracetaniline using hydrochloric acid in ethanol. Iodine will then be added to the molecule using iodine monochloride in the presence of acetic acid to yield 4-bromo-2-chloro-6-iodoaniline. Last, the 4-bromo-2-chloro-6-iodoaniline will be converted to 1-bromo-3-chloro-5-iodobenzene. This will take place by removing the amino group using nitrous acid to diazotize and hypophosphorous acid.

PART I

B. Main Reaction

Aniline —> 1-Bromo-3-chloro-5-iodobenzene

C. Mechanism

The overall reaction takes place using a six step synthesis reaction. Most of the reactions involve electrophillic aromatic substitution. Refer to the attached sheet for the reaction mechanism of the conversion of aniline to acetanilide.

D. Side Reactions

There are no side reactions.

E. Table of Reactants and Product(s)

Compound Molecular Weight (g/mol) Amount Used Moles Used (mol) Melting Point (ºC) Boiling Point (ºC) Hazards
Aniline 93.126 4.7 g 0.05 -6.0 184.0 Toxic, carcinogen
Hydrochloric Acid 36.46 4.5 mL -85.0 -114.0 Corrosive
Sodium Acetate Trihydrate 136.08 8.2 g 0.06 136.0 253.0 Irritant
Acetic Anhydride 102.1 6.5 g 0.065 -73.1 139.8 Corrosive
Acetanilide 135.17 113-115 304.0 Flammable, irritant
Part II

B. Main Reaction

Acetanilide + Br2 + CH3CO2H —> 4-Bromoacetanilide + 2-Bromoacetanilide + HBr

C. Mechanism

The substituent on the benzene ring, –NHCOCH3,is a ring activating group and thus is ortho and para directing. This allows bromination to occur at ortho and para positions. Refer to the attached sheet for the reaction mechanism of the conversion of acetanilide to 4-bromoacetanilide.

D. Side Reactions

To get rid of excess bromine, this sodium bisulfate is added to produce this reaction: HSO3- + Br2 + 3H2O —> HSO4- + 2 Br- + 2H­3O-

E. Table of Reactants and Product(s)

Compound Molecular Weight (g/mol) Amount Used Moles Used (mol) Melting Point (ºC) Boiling Point (ºC) Hazards
Acetanilide 135.17 113-115 304.0 Flammable, irritant
Bromine 79.904 -7.2 58.8 Corrosive, irritant
Acetic Acid 60.05 16.5 118.1 Corrosive, irritant
Sodium Bisulfate 138.07 315 Decomposes Irritant
Part III

B. Main Reaction

4-Bromoacetanilide + Cl2 —> 4-Bromo-2-chloroacetanilide + HCl

C. Mechanism

The substituents on the benzene ring, –NHCOCH3 and –Br,are both ortho and para directors. However, –NHCOCH3 is an activating group while –Br is mildly deactivating, so this favors chlorine addition ortho to –NHCOCH3. Refer to the attached sheet for the reaction mechanism of the conversion of 4-bromoacetanilide to 4-bromo-2-chloroacetanilide.

D. Side Reactions

HCl + NaClO3 —> HClO3 + NaCl

2NaCl + 2H2O —> Cl2 + H2 + 2NaOH

E. Table of Reactants and Product(s)

Compound Molecular Weight (g/mol) Amount Used Moles Used (mol) Melting Point (ºC) Boiling Point (ºC) Hazards
4-Bromoacetanilide 214.06     166-170   Irritant
Hydrochloric Acid 36.46     -85.0 -114.0 Corrosive
Acetic Acid 60.05     16.5 118.1 Corrosive, irritant
Sodium Chlorate 106.44     248 300 (decomposes)  
Part IV

B. Main Reaction

4-Bromo-2-chloroacetanilide + HCl + H2O + CH3CH2OH —> 4-Bromo-2-chloroanilinium chloride

4-Bromo-2-chloroanilinium chloride + NaOH + H2O —> 4-Bromo-2-chloroaniline + NaCl + H2O

C. Mechanism

Refer to the attached sheet for the reaction mechanism.

D. Side Reactions

There are no side reactions during this part of the synthesis.

E. Table of Reactants and Product(s)

Compound Molecular Weight (g/mol) Amount Used Moles Used (mol) Melting Point (ºC) Boiling Point (ºC) Hazards
4-Bromo-2-chloroacetanilide 248.51     70-72   Irritant
Ethanol 46.07     -114.3 78.4 Flammable
Hydrochloric Acid 36.46     -25 109 Corrosive
Sodium Hydroxide 39.997     318 1390 Irritant
4-Bromo-2-Chloroaniline 206.47     67-70   Irritant
Methanol 32.04     -97 64.7 Flammable, toxic
Part V

B. Main Reaction

4-Bromo-2-chloroanilinium chloride + ICl + CH3CO2H —> 4-bromo-2-chloro-6-iodoaniline

C. Mechanism

The reaction takes place via Sn2 substitution. Refer to the attached sheet for the reaction mechanism.

D. Side Reactions

There are no side reactions during this part of the synthesis.

E. Table of Reactants and Product(s)

Compound Molecular Weight (g/mol) Amount Used Moles Used (mol) Melting Point (ºC) Boiling Point (ºC) Hazards
4-Bromo-2-Chloroaniline 206.47     67-70   Irritant
Iodine Monochloride 162.35     27 97.4 Corrosive
Acetic Acid 60.05     16.5 118.1 Corrosive, irritant
Sodium Bisulfate 138.07     315 Decomposes Irritant

II. Post-Lab Report

Part I – Steps 1 Through 3

A. Experimental Procedure

The experimental procedure was followed pretty much as written. One change throughout was that the amount of reagents needed for the procedures had to be proportional to the amount of product recovered. Another change throughout was that the melting point of the products were never taken and a small sample was never submitted. During acetylation, acetic anhydride was not added to the filtrate to try to recover additional acetanilide. During bromination, 3 mL of methanol per gram of compound was added during recrystallization rather than 5 mL. Also, the bromine used was a weaker concentration than anticipated, so additional store-bought 4-bromoacetanilide was added to the product recovered. Finally, during chlorination, an excess of methanol was added while washing the beaker to filtrate the recrystallized product, so an excess of cold water was added to the filtrate to recover more 4-bromo-2-chloroacetanilide.

B. Observed Yield of Product

Weight of aniline: 4.7 g

Moles of aniline: 0.05

Observed weight of acetanilide: 5.122 g

Observed moles of acetanilide: 0.038

Observed yield of acetanilide from aniline: 76.0%

Theoretical weight of acetanilide: 6.76 g

Theoretical moles of acetanilide: 0.05


Observed weight of 4-bromoacetanilide: 4.7 g

Observed moles of 4-bromoacetanilide: 0.022

Observed yield of 4-bromoacetanilide from acetanilide: 57.9%

Theoretical weight of 4-bromoacetanilide: 8.13 g

Theoretical moles of 4-bromoacetanilide: 0.038


Observed weight of 4-bromo-2-chloroacetanilide: 4.0 g

Observed moles of 4-bromo-2-chloroacetanilide: 0.016

Observed yield of 4-bromo-2-chloroacetanilide from 4-bromoacetanilide: 72.7%

Theoretical weight of 4-bromo-2-chloroacetanilide: 5.47 g

Theoretical moles of 4-bromo-2-chloroacetanilide: 0.022


Observed yield of 4-bromo-2-chloroacetanilide from aniline: 32%

C. Calculations

(Moles of final product) / (Moles of starting material) * 100 = Observed yield

Moles of starting material = Theoretical moles of product

D. Conclusions

During these first three parts of the six-step synthesis, it was really important to do everything very deliberately and carefully. It was necessary to make sure every step was performed with precision in order to get a high yield in the end. If lab procedure was not followed exactly as described, product would most likely be lost. There are many factors that can lead to loss of eventual final product. Such factors include adding too much methanol during recrystallization, not using the precise amount of reagents required, and simply not being able to get all of the solutions and products transferred from filter paper to flask or from flask to flask. One of example of something that did happen during the synthesis that affected the yield was during bromination. The bromine used during bromination turned out to be of lesser concentration than expected, which gave a poor yield of product. This was uncontrollable, and store-bought 4-bromoacetanilide had to be added to the recovered product. The store bought 4-bromoacetanilide is not as pure as the recovered product, so this will affect the yield of product in the next steps of synthesis. Overall, precision was the most important factor in recovering a high percent yield.

The percent yields for the synthesis thus far are fairly low. From step to step, the average percent yield has been 68.9% and overall the percent yield from the beginning until the last completed step in the synthesis has been 32%. It is expected that the percent yield will keep going down from after each step because it is very hard to achieve a very high yield under the laboratory conditions. Under perfect conditions, the expected percent yield would be 100%, but is nearly impossible to accomplish that. The observed yield after each separate step does not seem very bad, with the average being nearly 70%, but that loss of product will add up over the course of the six steps. The theoretical moles for the product of each step is equal to the number of moles for the starting material because the starting material reacts to form the product in a 1:1 ratio for each step.

Part II – Steps 1 Through 6

A. Experimental Procedure

The experimental procedure was followed pretty much as written. One change throughout was that the amount of reagents needed for the procedures had to be recalculated to be proportional to the amount of product recovered. Another change throughout was that the melting point of the products were never taken and a small sample was never submitted. During amide hydrolysis, a second crop of 4-bromo-2-chloroaniline was not collected, which would have been performed by adding additional cold water to the filtrate. During iodination, a second crop of product was again not collected, which would have been performed by the same method described during amide hydrolysis.

B. Observed Yield of Product

Weight of 4-bromo-2-chloroacetanilide: 4.0 g

Moles of 4-bromo-2-chloroacetanilide: 0.016


Weight of 4-bromo-2-chloroaniline: 2.142 g

Moles of 4-bromo-2-chloroaniline: 0.010

Observed yield of 4-bromo-2-chloroaniline from 4-bromo-2-chloroacetanilide: 62.5%


 

Weight of 4-bromo-2-chloro-6-iodoaniline:

Moles of 4-bromo-2-chloro-6-iodoaniline:

Observed yield of 4-bromo-2-chloro-6-iodoaniline from 4-bromo-2-chloroaniline:


 

Observed yield of 4-bromo-2-chloro-6-iodoaniline from 4-bromo-2-chloroacetanilide:

Observed yield of 4-bromo-2-chloro-6-iodoaniline from aniline: 0.05 moles aniline

C. Calculations

(Moles of final product) / (Moles of starting product) * 100 = Observed yield

D. Conclusions

The percent yield through the first five steps of the synthesis is %. This percentage is fairly low, but the percent yield for the sixth step, deamination, is typically very low, so this would make the overall percent yield even lower. Even with a typical low yield for deamination, it is most likely that some final product would have been recovered if deamination had taken place. Amide hydrolysis and iodination were performed very carefully and precisely, but the yields were still not very high. This shows how hard it can be to achieve high yields during a synthesis in laboratory conditions.

The theoretically yields from starting material to product should have been a 1:1 mole ratio throughout the synthesis. These theoretical yields were not nearly achieved however, for various reasons. The steps where the most product was lost were during transfers and recrystallization. It was difficult to transfer every bit of product between filter paper and flasks. During recrystallization, product could have easily evaporated away if the product in methanol was heated too much. It was difficult to control and measure the heat during this step.

Amide hydrolysis was performed so that iodine would be directed ortho to the previously acetamido group during iodination. The amino group generated during amide hydrolysis is more activating than the acetamido group. Iodine is less electrophilic than bromine and chlorine, so it needed a more activating ring in order to attach. The acetamido group was better for bromination and chlorination because they required a less activated ring and the reaction could be controlled to give monosubstitution. There was no possibility of disubstitution during iodination with the amino group present.