Review
The synthesis of O-(4-methyl)-phenyl-N-(9’-acridinyl)-hydroxylamine consists of four steps that are similar to O-phenyl-N-(9’-acridinyl)-hydroxylamine. The first step consists of the synthesis of diaryliodonium triflate. The reactants are p-iodotoluene and toluene. Diaryliodonium triflate is an unstable product that cannot be allowed to sit for longer than a few hours. The second step entails of the production of N-(4-methyl)-phenyloxyphthalimide in which the reactants are diaryliodonium triflate and N-hydroxyphthalimide. While the product of step 1 in unstable, N-(4-methyl)-phenyloxyphthalimide is stable and may be left in the lab for future use. Step 3 involves the hydrolysis of N-(4- methyl)-phenyloxyphthalimide. After this step is concluded, a product named O-(4-methyl)-phenylhydroxylamine. The last step consists of the production of the final compound. It is the synthesis of O-(4-methyl)-phenyl-N-(9’-acridinyl)-hydroxylamine with the reactants being O-(4-methyl)-phenylhydroxylamine and 9-chloroacridine.
Synthesis of Diaryliodonium Triflate
The synthesis of diaryliodonium triflate comprises of reactants being p-iodotoluene and toluene. The procedure being used can be referenced from Deselm’s thesis (DeSelm, 2016). A 25 milliliter round bottom flask is taken and a stir bar is placed in it. After a stopper is placed around the round bottom flask and it is placed in a fume hood, Argon gas is allowed to flow through the flask preventing water vapor from interfering with the reaction. Then, 2 milliliters of dry dicholormethane and 121 milligrams of mCPBA are measured and added to the round bottom flask. Once completed, 0.1 grams of p-iodotoluene and 0.05 milliliters of toluene are added to the round bottom flask and are allowed to stir. Next, 120 microliters of triflic acid are added to the flask. This solution is allowed to stir for 10 minutes at room temperature. The solution is then rotatory evaporated at a temperature around 20 degrees celsius until a dry solid is left over. This product is then dissolved using 2 milliliters of diethyl ether and is left to stir in the round bottom flask for 10 minutes and then the entire solution is placed in the refrigerator for at least 30 minutes. This concludes the synthesis of diaryliodonium triflate.
Synthesis of N-(4-methyl)-phenyloxyphthalimide
The synthesis of N-(4-methyl)-phenyloxyphthalimide consists of reactants being diaryliodonium triflate and N-hydroxyphthalimide. The procedure being followed for the synthesis of diaryliodonium triflate and N-hydroxyphthalimide is being referenced from Deselm’s thesis (DeSelm, 2016). First, 2 milliliters of DMF is added to new 25 milliliters round bottom flask with a stir bar placed in it. Argon gas is also allowed to flow through the round bottom flask. Once completed, 62 milligrams of t-BuOK and 82 milligrams of hydroxyphthalimide is measured and dissolved into the round bottom flask. This reaction is then allowed to stir at room temperature for 10 minutes. Next, the diaryliodonium triflate that was produced in step one is taken out of the refrigerator and added to the round bottom flask. Since the entirety of diaryliodoium triflate is unable to come out of the flask, the flask is rinsed in DMF to get the rest of the product out and then is added to the new round bottom flask. The solution is then heated to around 60 degrees celsius and left for approximately one hour. Once the hour has passed, the solution is allowed to cool to room temperature and then is poured into a separatory funnel. Then about 20 milliliters of deionized water and 20 milliliters of ethyl acetate are measured and added to the separatory funnel. The aqueous layer is then separated from the organic layer. The steps involving the separatory funnel are repeated as needed until most of the aqueous layer is removed. In the very last repetition of the steps involving the separatory funnel, about 10 milliliters of brine solution is added to cause the solution to separate even more. Once completed, anhydrous sodium sulfate is repeatedly added and stirred to the solution until the water particles were absorbed. It can be concluded that all the water particles are absorbed when the anhydrous sodium sulfate look powdery in the solution. Then a gravity filtration system is set up and used to filter the anhydrous sodium sulfate out of the solution. A little bit of ethyl acetate was added into the solution to get the entirety of the solution out. This was then left in the hood to let the ethyl acetate evaporate.
Use of the H-NMR
The product created in step one of this reaction, diaryliodonium triflate, is an unstable product that cannot be left untouched for long. However, the product of step two, N-(4-methyl)-phenyloxyphthalimide, is a stable product that can be left in the lab without reacting to the water molecules in the atmosphere. This allows an H-NMR to be taken on the product. It is crucial to take an H-NMR at step two in order to verify that it is the correct compound so that steps three and four may proceed successfully. If the correct compound was produced, the reaction may continue however if the N-(4-methyl)-phenyloxyphthalimide was not produced, steps one and two will have to be repeated.
Hydrolysis of N-(4-methyl)-phenyloxyphthalimide
The third step consists of the hydrolysis of N-(4-methyl)-phenyloxyphthalimide. Several different procedures have been found to complete this procedure. However, the one that will be followed can be found in Deselm’s thesis (DeSelm, 2016). This product can be purchased online however it is more cost efficient and feasible if it is produced. N-(4-methyl)-phenyloxyphthalimide is added to a mixture of hydrochloric acid. Next, 15 milliliters of glacial acetic acid is added. The solution is then refluxed for two hours. Once completed, the excess acid in the solution is removed via a rotary evaporator. Afterwards, the product is scraped into a 50 milliliter erlenmeyer flask. If any residue is left over, it can be rinsed with deionized water and then added to the flask. Then, sodium hydroxide is added in dropwise addition using a pipette into the solution. Next, the solution is transferred into a separatory funnel. To the separatory funnel, 30 milliliters of dichloromethane and deionized water is added and shaken to separate the aqueous layer from the organic layer. The steps involving the separatory funnel are repeated as needed until most all of the non-organic compounds have been discarded. Next, the anhydrous sodium sulfate is added, as necessary, to the solution to remove any water particles. The mixture is then filtered through a gravity filtration to remove the anhydrous sodium sulfate. Afterwards, the solution is bubbled through hydrochloric acid. It is then left to stir for at least 30 minutes and then suction filtered. The solution is then set aside to dry overnight which then completes the hydrolysis of N-(4-methyl)-phenyloxyphthalimide.
Synthesis of O-(4-methyl)-phenyl-N-(9’-acridinyl)-hydroxylamine
The synthesis of O-(4-methyl)-phenyl-N-(9’-acridinyl)-hydroxylamine is the final step needed to complete the production of the novel anti-tumor drug. The procedure used for this step can be referenced from Deselm’s research paper (DeSelm, 2016). First, 3.3 grams of phenol is added to a round bottom with a stir bar. It is then heated to 88 degrees celsius and stirred for a period of 6 hours. Once the reaction is at its most vigorous, it is cooled to room temperature. The product is then added to 50 milliliters of dichloromethane which is then placed in a separatory funnel. Afterwards, 100 milliliters of sodium hydroxide is also placed into the separatory funnel, which will then allow the aqueous layer to separate from the organic layer. The steps involving the separatory funnel may be repeated as many times as necessary. Once completed, the solution is dried with anhydrous magnesium sulfate and then gravity filtered to remove any water from the solution. In order to remove any remaining solvent, the solution is then rotary evaporated. This concludes the synthesis of O-(4-methyl)-phenyl-N-(9’-acridinyl)-hydroxylamine.
The synthesis of O-(4-methyl)-phenyl-N-(9’-acridinyl)-hydroxylamine consists of four steps that are similar to O-phenyl-N-(9’-acridinyl)-hydroxylamine. The first step consists of the synthesis of diaryliodonium triflate. The reactants are p-iodotoluene and toluene. Diaryliodonium triflate is an unstable product that cannot be allowed to sit for longer than a few hours. The second step entails of the production of N-(4-methyl)-phenyloxyphthalimide in which the reactants are diaryliodonium triflate and N-hydroxyphthalimide. While the product of step 1 in unstable, N-(4-methyl)-phenyloxyphthalimide is stable and may be left in the lab for future use. Step 3 involves the hydrolysis of N-(4- methyl)-phenyloxyphthalimide. After this step is concluded, a product named O-(4-methyl)-phenylhydroxylamine. The last step consists of the production of the final compound. It is the synthesis of O-(4-methyl)-phenyl-N-(9’-acridinyl)-hydroxylamine with the reactants being O-(4-methyl)-phenylhydroxylamine and 9-chloroacridine.
Synthesis of Diaryliodonium Triflate
The synthesis of diaryliodonium triflate comprises of reactants being p-iodotoluene and toluene. The procedure being used can be referenced from Deselm’s thesis (DeSelm, 2016). A 25 milliliter round bottom flask is taken and a stir bar is placed in it. After a stopper is placed around the round bottom flask and it is placed in a fume hood, Argon gas is allowed to flow through the flask preventing water vapor from interfering with the reaction. Then, 2 milliliters of dry dicholormethane and 121 milligrams of mCPBA are measured and added to the round bottom flask. Once completed, 0.1 grams of p-iodotoluene and 0.05 milliliters of toluene are added to the round bottom flask and are allowed to stir. Next, 120 microliters of triflic acid are added to the flask. This solution is allowed to stir for 10 minutes at room temperature. The solution is then rotatory evaporated at a temperature around 20 degrees celsius until a dry solid is left over. This product is then dissolved using 2 milliliters of diethyl ether and is left to stir in the round bottom flask for 10 minutes and then the entire solution is placed in the refrigerator for at least 30 minutes. This concludes the synthesis of diaryliodonium triflate.
Synthesis of N-(4-methyl)-phenyloxyphthalimide
The synthesis of N-(4-methyl)-phenyloxyphthalimide consists of reactants being diaryliodonium triflate and N-hydroxyphthalimide. The procedure being followed for the synthesis of diaryliodonium triflate and N-hydroxyphthalimide is being referenced from Deselm’s thesis (DeSelm, 2016). First, 2 milliliters of DMF is added to new 25 milliliters round bottom flask with a stir bar placed in it. Argon gas is also allowed to flow through the round bottom flask. Once completed, 62 milligrams of t-BuOK and 82 milligrams of hydroxyphthalimide is measured and dissolved into the round bottom flask. This reaction is then allowed to stir at room temperature for 10 minutes. Next, the diaryliodonium triflate that was produced in step one is taken out of the refrigerator and added to the round bottom flask. Since the entirety of diaryliodoium triflate is unable to come out of the flask, the flask is rinsed in DMF to get the rest of the product out and then is added to the new round bottom flask. The solution is then heated to around 60 degrees celsius and left for approximately one hour. Once the hour has passed, the solution is allowed to cool to room temperature and then is poured into a separatory funnel. Then about 20 milliliters of deionized water and 20 milliliters of ethyl acetate are measured and added to the separatory funnel. The aqueous layer is then separated from the organic layer. The steps involving the separatory funnel are repeated as needed until most of the aqueous layer is removed. In the very last repetition of the steps involving the separatory funnel, about 10 milliliters of brine solution is added to cause the solution to separate even more. Once completed, anhydrous sodium sulfate is repeatedly added and stirred to the solution until the water particles were absorbed. It can be concluded that all the water particles are absorbed when the anhydrous sodium sulfate look powdery in the solution. Then a gravity filtration system is set up and used to filter the anhydrous sodium sulfate out of the solution. A little bit of ethyl acetate was added into the solution to get the entirety of the solution out. This was then left in the hood to let the ethyl acetate evaporate.
Use of the H-NMR
The product created in step one of this reaction, diaryliodonium triflate, is an unstable product that cannot be left untouched for long. However, the product of step two, N-(4-methyl)-phenyloxyphthalimide, is a stable product that can be left in the lab without reacting to the water molecules in the atmosphere. This allows an H-NMR to be taken on the product. It is crucial to take an H-NMR at step two in order to verify that it is the correct compound so that steps three and four may proceed successfully. If the correct compound was produced, the reaction may continue however if the N-(4-methyl)-phenyloxyphthalimide was not produced, steps one and two will have to be repeated.
Hydrolysis of N-(4-methyl)-phenyloxyphthalimide
The third step consists of the hydrolysis of N-(4-methyl)-phenyloxyphthalimide. Several different procedures have been found to complete this procedure. However, the one that will be followed can be found in Deselm’s thesis (DeSelm, 2016). This product can be purchased online however it is more cost efficient and feasible if it is produced. N-(4-methyl)-phenyloxyphthalimide is added to a mixture of hydrochloric acid. Next, 15 milliliters of glacial acetic acid is added. The solution is then refluxed for two hours. Once completed, the excess acid in the solution is removed via a rotary evaporator. Afterwards, the product is scraped into a 50 milliliter erlenmeyer flask. If any residue is left over, it can be rinsed with deionized water and then added to the flask. Then, sodium hydroxide is added in dropwise addition using a pipette into the solution. Next, the solution is transferred into a separatory funnel. To the separatory funnel, 30 milliliters of dichloromethane and deionized water is added and shaken to separate the aqueous layer from the organic layer. The steps involving the separatory funnel are repeated as needed until most all of the non-organic compounds have been discarded. Next, the anhydrous sodium sulfate is added, as necessary, to the solution to remove any water particles. The mixture is then filtered through a gravity filtration to remove the anhydrous sodium sulfate. Afterwards, the solution is bubbled through hydrochloric acid. It is then left to stir for at least 30 minutes and then suction filtered. The solution is then set aside to dry overnight which then completes the hydrolysis of N-(4-methyl)-phenyloxyphthalimide.
Synthesis of O-(4-methyl)-phenyl-N-(9’-acridinyl)-hydroxylamine
The synthesis of O-(4-methyl)-phenyl-N-(9’-acridinyl)-hydroxylamine is the final step needed to complete the production of the novel anti-tumor drug. The procedure used for this step can be referenced from Deselm’s research paper (DeSelm, 2016). First, 3.3 grams of phenol is added to a round bottom with a stir bar. It is then heated to 88 degrees celsius and stirred for a period of 6 hours. Once the reaction is at its most vigorous, it is cooled to room temperature. The product is then added to 50 milliliters of dichloromethane which is then placed in a separatory funnel. Afterwards, 100 milliliters of sodium hydroxide is also placed into the separatory funnel, which will then allow the aqueous layer to separate from the organic layer. The steps involving the separatory funnel may be repeated as many times as necessary. Once completed, the solution is dried with anhydrous magnesium sulfate and then gravity filtered to remove any water from the solution. In order to remove any remaining solvent, the solution is then rotary evaporated. This concludes the synthesis of O-(4-methyl)-phenyl-N-(9’-acridinyl)-hydroxylamine.