The Two-step Organic Synthesis of 4-bromoacetanilide and How Green Chemistry Principles Apply

Abstract

This experiment was completed with the purpose to utilize the principles of green chemistry in the analysis of the two-step organic synthesis of 4-bromoaceanilide. This experiment was relevant because of the importance of green chemistry principles in regards to environmental and human health safety. It was found that it was still possible to obtain a suitable percent yield of 68% through the altered reaction sequence (Table 1). The class and individual yields both showed that it is possible to perform the alternate, greener reaction and still obtain desirable results. The spectroscopy data was analyzed in order to confirm the identity of acetanilide and 4-bromoacetanilide. The alternate reaction showed that it was the more optimal reaction than the standard one, due to the principles of green chemistry that it followed. These principles are important to human health and the protection of the environment and the altered reaction used in lab was a step in the right direction in making reactions more chemically green.

Introduction

The purpose of this experiment was to use green chemistry principles to analyze the two-step organic synthesis of 4-bromoacetanilide. The standard reaction sequence discussed in this experiment produces harmful byproducts and waste.3 The cost to dispose of hazardous substances properly is high.2 Green chemistry principles are used in order to create a better and safer reaction sequence. An acyl transfer reaction is used in this experiment in order to form acetanilide from aniline. This acyl transfer reaction is used as a protecting group, which enables acetanilide to undergo a mono-substitution instead of multiple substitutions.1 Since acetanilide is more acidic it will facilitate the reaction between HOCl and NaBr since these reactions are generally acid assisted ones.4 This implements the green chemistry principles of prevention and use of less hazardous chemicals. The balanced equations for the two-step synthesis performed in lab are shown below. The first reaction forms the acetanilide compound while the second forms the 4-bromoacetanilide.

Methods

Acetylation Reaction

First, 2mL (22 mmol) of aniline and 4mL (69 mmol) of glacial acetic acid were mixed together in a dry, clean 25 mL round bottom flask. A stir bar was incorporated into the mixture and the air condenser and adapter were secured to the flask. The mixture was brought to a boil around 370-430 °C while being stirred. During this time the condensation ring movement was carefully observed. When the condensation ring had risen halfway to two-thirds up the condenser the heat was lowered by 5-10 °C. At this time the reaction was refluxed for 90 minutes and the height of the condensation ring was once again carefully monitored.

The reaction was removed from the heat after 90 minutes and cooled before it was poured into 30 mL of cold ice water inside a 100 mL beaker. This mixture was cooled and stirred in a bath of ice water until crystallization was complete. The crystals were then gathered with a Büchner filter and washed twice with 10 mL of ice water. Once the acetanilide crystals were dry, they were massed to obtain 1.808 g (61%) of a white solid: mp 108-111 °C with decomposition [lit.5 mp 113-114 °C]; IR 3291, 3067, 3027, 1662, 1499, 1262 cm-1; 1H NMR (500 MHz, CDC13) δ 2.16 (3H, s), 7.11 (1H, t), 7.31 (2H, m), 7.5 (2H, d), 7.65 (1H, s); 13C NMR (125.7 MHz, CDC13) δ 24.6, 120.1, 124.5, 129.1, 138, 168.8.

Bromination Reaction

First, 1.0 g (7.4 mmol) of acetanilide was mixed with 1.8 g (17.5 mmol) of NaBr in a 125 mL Erlenmeyer flask along with 6 mL of 95% ethanol, 5 mL of acetic acid, and a stir bar. This reaction was stirred in a bath of ice water for 5 minutes. After completion, 10.7 mL (7.8 mmol) of NaOCl were added to the mixture and the reaction was removed from the ice water bath after being stirred for 5 additional minutes. After allowing the mixture to set for 15 minutes it was once again cooled on a bath of ice water. A solution was prepared of 1.0 g of sodium thiosulfate added to 1.0 g of sodium hydroxide in 10 mL of distilled water. This preparation was incorporated into the reaction mixture and then mixed for 15 minutes. The crude product that formed was then gathered through vacuum filtration and washed with 10 mL of distilled water. Once dry, 50% ethanol was implemented in order to recrystallize the crude product. The recrystallized 4-bromoacetanilide product was collected and massed to obtain 1.076 g (68%) of a white solid: mp 167-168 °C with decomposition [lit.5 mp 167-169 °C]; IR 3300, 3064, 2928, 1667, 1536, 1258 cm-1; 1H NMR (500 MHz, DMSO) δ 2.04 (3H, s), 7.47 (2H, d, J = 2.5 Hz), 7.57 (2H, d, J = 2.5 Hz), 10.06 (1H, s); 13C NMR (125.7 MHz, DMSO) δ 24.4 (2.04), 114.9, 121.3 (7.57), 131.9 (7.47), 139.1, 168.9.

Table 1. The table below shows the yields and percent yields of the class and individual data of the acetanilide and 4-bromoacetanilide products. It can be seen that the average class acetanilide yield was 1.84 grams whereas the individual yield was 1.808 grams. The lower individual yield is why the overall individual percent yield is lower than the class value. The standard deviation of the acetanilide class yield was 0.23. This means that there was almost no deviation from the average, which means that the individual yield was actually below average. The standard deviations of the class percent yields for acetanilide and 4-bromoacetanilide are 7.9 and 12.2 respectively. This means that there were a greater number of groups that deviated away from the actual average, which shows that the individual percent yields for both substances were comparatively similar to the average.

Table 2. The table below shows the frequencies of the IR spectrum of Acetanilide along with their assignments. The frequency at 3291 cm-1 was assigned to an NH bond, which is consistent with the NH bond that was part of the amide at the 1662 cm-1 frequency. This amide group also confirms the products identity of acetanilide.

Table 3. The table below shows the 13C NMR Spectrum peaks for acetanilide in ppm along with the number of hydrogen atoms attached and the assignments of the peaks. The structure to the left of the table shows where each peak is assigned on the structure. The number of hydrogen atoms attached is consistent with the assignments to the structure for each different peak. This confirms the identity of acetanilide instead of 4-bromoacetanilide due to there being 1 hydrogen atom attached to carbon 6, whereas in 4-bromoacetanilide there were 0 hydrogen atoms attached.

Table 4. The table below shows the 1H NMR Spectrum for acetanilide along with the structure that corresponds to the assignments. The values of the peaks in ppm are given along with the number of hydrogen atoms attached at each different peak. The values of the peaks are consistent with the values given in the starting information. The amount of hydrogen atoms that correspond to each different peak is also consistent with its corresponding assignment in the structure of acetanilide. The identity of acetanilide is further confirmed due to the hydrogen atom attached to the carbon at position E, whereas in 4-bromoacetanilide there was not a hydrogen atom at that location.

4-bromoacetanilide Spectroscopy Tables

Table 5. The table below shows the frequencies of the IR spectrum of 4-bromoacetanilide along with their assignments. The frequency at 3300 cm-1 was assigned to an NH bond, which is consistent with the NH bond that was part of the amide at the 1667 cm-1 frequency. This amide group also confirms the products identity as 4-bromoacetanilide.

Table 6. The table below shows the 13C NMR Spectrum peaks for 4-bromoacetanilide in ppm along with the number of hydrogen atoms attached and the assignments of the peaks. The structure to the left of the table shows where each peak is assigned on the structure. The number of hydrogen atoms attached is consistent with the assignments to the structure for each different peak. This confirms the identity of 4-bromoacetanilide instead of acetanilide due to there being 0 hydrogen atoms attached to carbon 6, whereas in acetanilide there was 1 hydrogen atom attached.

Table 7. The table below shows the 1H NMR Spectrum for 4-bromoacetanilide along with the structure that corresponds to the assignments. The values of the peaks in ppm are given along with the number of hydrogen atoms attached at each different peak. The values of the peaks are consistent with the values given in the starting information. The amount of hydrogen atoms that correspond to each different peak is also consistent with its corresponding assignment in the structure of 4-bromoacetanilide. The identity of 4-bromoacetanilide is further confirmed due to there no longer being a hydrogen atom attached to the carbon that is now attached to bromine, whereas in acetanilide there was a hydrogen atom at that location. The coupling information from the COSY is also shown in the Mult. column.

Table 8. The table below shows the HSQC data for 4-bromoacetanilide. The 13C NMR peaks are shown along with their corresponding 1H NMR peaks if applicable. Only three 1H NMR peaks are shown since to the final peak was attached to a nitrogen atom instead of a carbon. This confirms the identity of the 4-bromoacetanilide product.

Discussion

Both of the reactions performed in this experiment exhibit principles of green chemistry. The main guiding principles shown are prevention, the use of less hazardous chemical syntheses, safer solvents and auxiliaries, efficiency, reduced derivatives, and inherently safer chemistry for accident prevention.5 Prevention is an important principle to use in this discussion because of the experiments change from the more hazardous standard procedure to the safer procedure that was actually performed. Along these lines, the use of less hazardous chemical syntheses and safer solvents and auxiliaries are two key factors in analyzing the green chemistry of this experiment. These factors show the negative qualities of the standard procedure and exemplify the positive qualities of the altered one. Efficiency can be seen in the standard procedure and will be explained in more detail later on. The green chemistry principle of reduced derivatives is displayed in both reactions’ use of protecting groups and for this reason it is included in this discussion. The final guiding principle for discussion is the use of inherently safer chemistry for accident prevention. This principle can be used to examine how the altered reaction is more chemically safe compared to the standard procedure. These are the main guiding principles that can be used to analyze the two reaction sequences and their ability to be considered green.

The first principle for discussion is prevention. In the standard procedure for the formation of 4-bromoacetanilide, HBr was produced as a byproduct along with the possibility of unreacted Br2 being present after the reaction was completed. This is a problem due to the fact that HBr is a strong, toxic acid and Br2 is corrosive and toxic.5 These are not substances that are good to have lying around after a reaction is completed. The altered reaction sequence however, fixes this problem. In the altered reaction, safer reagents are used in order to only produce water and NaCl as byproducts. Water can be easily returned to the environment and NaCl is a much safer alternative than Br2 or HBr. Therefore, the altered reaction sequence is more chemically green than the standard procedure in regards to the principle of prevention.

Along the lines of prevention are the principles of using less hazardous chemical syntheses and safer solvents and auxiliaries. The standard reaction uses materials like acetic anhydride and bromine, which are reactive and toxic to humans and the environment. The standard reaction then generates more toxic and corrosive materials such as HBr and Br2. This displays the standard reaction’s total disregard for green chemistry. The materials implemented in the altered reaction sequence are not entirely safe and harmless either. Bleach is used as the source of HOCl, instead of acetic anhydride. Being able to avoid acetic anhydride is beneficial, but bleach is toxic to humans and the environment as well and can be deadly if mixed with the wrong substances. The altered reactions use of NaBr as a reagent on the other hand, is positive because of its low toxicity. Once again, the altered reaction also generates safer byproducts that are not as harmful as the ones produced in the standard reaction. Even with the use of bleach, the altered reaction is still considered to be more chemically green than the standard reaction sequence.

Two green chemistry principles that both reaction sequences show are efficiency and reduced derivatives. Aside from the production of toxic materials in the standard reaction sequence, both reactions run very well on their own.5 It is possible to attain a high percent yield from these reactions and receive a pure compound that has an almost identical melting point as the literature value.3 Efficiency is a big part of green chemistry since less energy and resources have to be used in order to reach the desired product. Both reactions also display the principle of reduced derivatives. One reagent used in both reaction sequences is aniline. Since aniline heavily activates the benzene ring it is attached to this can cause the ring to undergo numerous substitution reactions. This can be problematic since multiple substitutions can produce uncontrollable side products, which could cause various complications. To counteract this, the amino group can be acetylated, which would cause it to only undergo mono-substitution. The acyl group acts as a protecting group in both of these reaction sequences. Even though the protecting groups help to not generate other byproducts and waste, they require an additional step, which goes against the principle of reduced derivatives.1

The final green chemistry principle used for discussion is the use of inherently safer chemistry for accident prevention. The aim of this principle is to utilize substances that are relatively safe and that minimize the possibility of chemical accidents occurring.5 This principle is not displayed in the standard procedure at all. The materials used and generated in that procedure such as HBr, unreacted Br2, and acetic anhydride can all be toxic and detrimental to the environment and human health. The only material used in the altered reaction that has the potential to be harmful to the environment and health is bleach. The other materials such as water and NaBr are safer than their counterparts and can be returned to the environment easily. This principle shows that the altered reaction once again is more chemically green than the standard sequence.

Ultimately, after analyzing these reactions with regards to green chemistry it can be seen that the standard reaction sequence is not chemically green at all. The toxic materials used produce toxic by products, which is not what green chemistry is about. A protecting group also has to be added which involves another step and is the opposite of reducing derivatives. It is not perfectly non-green however. The standard reaction is chemically efficient and can produce desired results.5 The altered reaction sequence performed in lab is the better option of the two. It implements safer starting materials to attain safer and more benign byproducts. Even though the altered reaction sequence is greener than the standard, it is not a perfect example of green chemistry. The reaction uses bleach as one of its materials, which is toxic to human health and the environment. A protecting group also has to be added on in order to permit mono-substitution. This is another step and goes against the principle of reducing derivatives. Overall, the altered reaction sequence provides more advantages in the area of green chemistry than the standard sequence, and it is a step in the right direction in utilizing green chemistry techniques to protect human health and the environment.

Conclusions

The completion of this experiment has given me newfound knowledge that I can take into future experiments and courses. Before this experiment, the principles of green chemistry had been touched on, but I did not fully realize the importance of these principles in chemistry. This experiment showed me the importance of making reactions green in order to reduce waste and protect the environment and health of individuals. I realized how harmful it could be if the standard procedure talked about in lab were performed on an industrial scale. Many harmful byproducts and waste would be produced. I now know that it is important to the health of the environment and laboratory workers to start looking for new ways to make reactions more chemically green.