Aisha Green Bupropion HCL Synthesis Lab Report Abstract Wellbutrin and Zyban are well known pharmaceuticals for the treatment of nicotine addiction1. The drugs are comprised of bupropion hydrochloride salt. Bupropion hydrochloride salt is created through the alpha bromination of m-chloropropiophenone, an SN2 reaction adding t-butyl, and pronation from HCl. The salt was then analyzed through HNMR to verify the structure of the compound that was formed. A yield of 65% was recovered from the reaction. Overall, the experiment demonstrated the process of pharmaceutical synthesis and synthesis efficiency. Introduction Bupropion hydrochloride salt an ingredient in medications such as Zyban and Wellbutrin which are prescribed as antidepressants2. Zyban and Wellbutrin work to suppress the reuptake of serotonin and norepinephrine, which can be used as a therapy of depression and smoking cessation. The pharmaceutical can be used as a treatment for nicotine addiction 1. The synthesis illustrates the ideas of pharmaceutical synthesis and synthesis efficiency. For a drug to be produced it has to be synthesized without producing much waste. In this experiment, a one-pot synthesis of m-chloropropiophenone into a bupropion hydrochloride salt was performed as shown in Figure 1. Figure 1: Synthesis of bupropion hydrochloride The reaction mechanism is shown in Figure 2 depicting step 1 where the ketone undergoes alpha bromination and is converted into a bromoketone. Then in step 2 there is a SN2 displacement of the bromine by the t-BuNH2. Finally, in step 3, there is conversion into ammonium hydrochloride salt through a reaction with HCL. NMP is used as the solvent for animation because generates a faster reaction. Figure 2: Reaction mechanism of bupropion hydrochloride synthesis This study source was downloaded by 100000835139325 from CourseHero.com on 05-31-2022 03:33:55 GMT -05:00 https://www.coursehero.com/file/65199491/Bupropion-HCl-synthesis-lab-reportdocx/ Results and Discussion The bromine turned a lighter yellow color compared to the drops of bromine that was added. There was a total of 8ml of distillate collected from the condensation reaction. The solution turned the pH paper a dark pink/purple color. The crystals formed were a light-yellow color instead of desired white crystals of bupropion hydrochloride. Figure 3 illustrates the calculations for theoretical yield and 65% yield. The theoretical yield for the experiment is 1.63 grams of bupropion hydrochloride because the molecular weight of the product is multiplied by the number of moles in the reagents. If there was only an actual yield of 65% then the yield for the experiment would be around 1.06 grams of bupropion hydrochloride recovered. Figure 3: Theoretical and 65% yield calculations This study source was downloaded by 100000835139325 from CourseHero.com on 05-31-2022 03:33:55 GMT -05:00 https://www.coursehero.com/file/65199491/Bupropion-HCl-synthesis-lab-reportdocx/ Even though 100% recovery would be the desired outcome, that does not always happen due to things like errors or the favorability of a reaction. Some things that may have caused a yield of only 65% may be that the bromine did not reach a light-yellow color meaning that the reaction did not go through to completion. Another source of error is not adding the bromine in the solvent in drops because if too much bromine was added it may react with other molecules or itself. Lastly, there was not 100% recovery because some of the salt was stuck in the flask reducing the yield. Some of the major plot points of the H NMR data is the singlet at 1.28ppm that is integrating for 9 protons indicating the tertbutyl group. Another reading that stands out is the doublet integrating 1 proton around 2.5ppm. There are also four very close readings that are around 7-8ppm that integrate for 1 hydrogen each indicating a benzene ring. This study source was downloaded by 100000835139325 from CourseHero.com on 05-31-2022 03:33:55 GMT -05:00 https://www.coursehero.com/file/65199491/Bupropion-HCl-synthesis-lab-reportdocx/ The major readings on the C NMR plot would be the large reading at 28.4ppm indicating the tertbutyl group attached to the molecule. Another important reading is 193.1ppm indicating a carbon attached to a very electronegative atom. Lastly there are the five readings that are close together ranging from 126-183ppm indicating a benzene ring in the molecule. Conclusion This study source was downloaded by 100000835139325 from CourseHero.com on 05-31-2022 03:33:55 GMT -05:00 https://www.coursehero.com/file/65199491/Bupropion-HCl-synthesis-lab-reportdocx/ The experiment used many useful chemistry techniques such as distillation, running a TLC plate, vacuum filtration, separation, and H NMR to create the product of bupropion hydrochloride. The reaction worked by alpha bromination of a ketone, an SN2 reaction of tbutylamine, and protonation into a salt using HCL to get a more stable, longer lasting product. The experiment had a yield of 1.06 grams meaning that there was a 65% yield, compared to the 1.63 grams that was expected. One reason the yield was decreased may have been due to not letting the reaction heat long enough meaning that it did not go through to completion and not yielding as much product. Overall, the experiment demonstrated the process of pharmaceutical synthesis and synthesis efficiency. Experimental This experiment involved taking m-chloropropiophenone then converting it into bupropion hydrochloride salt through a series of reactions. First one gram of mchloropropiophenone was dissolved in 5ml of CH2Cl2. Next, a few drops of 1M Br2 solution was added to the CH2Cl2 in single drops allowing the color to fade. The reaction was heated slightly, and 6 ml of bromine solution was added in drops. After all the bromine was added the reaction mixed for 15 minutes. A TLC plate of 1:1 DCM:hexanes was made to monitor the rate of the reaction. The CH2Cl2 was then removed by heating the reaction slightly. Next, 5ml of NMP was added followed by 5ml of t-butylamine. Then, the flask was heated in a warm water bath stirring for 15 min. The contents were then transferred into a separatory funnel adding 25ml of water, then the mixture was extracted with 10ml of ether 3 times. The ether extracts were then washed with 10ml of water, dried with anhydrous sodium sulfate, and chilled in an ice bath. Finally, 5.93mmols of a 4M HCL solution was added and crystals will begin to form. Once the crystals formed, they were collected, washed with ether and dried. Lastly, an H NMR reading was obtained. Post-lab questions 1. What would happen if you rinse the final crystals with water instead of Ether? a. Nothing would happen if the crystals were rinsed with water versus ether. The bupropion hydrochloride salt is not soluble in either solvent. The solvents will dissolve the impurities that are formed within the crystals and not the crystals themselves because the crystals are insoluble in those solvents. 2. What is the purpose of forming ammonium salts of organic compounds used as medicine? a. The purpose of forming ammonium salts in medicine is to reactivity because the ammonium salt is less reactive thus masking the reactivity of the product. This is done to allow the tablets to be stable for longer and not degrade. 3. Describe how your extraction would be different if you were using Ethyl acetate instead of ether? a. The extraction would not be different using ethyl acetate as the extraction solvent instead of ether. Since ethyl acetate and ether both have a lower density when compared to water. This means that the ether and acetate will be the top layer of the extraction with the product and the aqueous layer will be on the This study source was downloaded by 100000835139325 from CourseHero.com on 05-31-2022 03:33:55 GMT -05:00 https://www.coursehero.com/file/65199491/Bupropion-HCl-synthesis-lab-reportdocx/ bottom. But since the density of ethyl acetate is closer to water the compounds may take longer/harder to separate when compared to ether. References 1. Perrine, Daniel M.; Ross, Jason T.; Nervi, Stephen J.; Zimmerman, Richard H. A Short, One-Pot Synthesis of Bupropion (Wellbutrin, Zyban). Journal of Chemical Education 2000, 77 (11), 1479, DOI: 10.1021/ed077p1479 2. National Library of Medicine. PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/Bupropion (accessed May 1, 2020) This study source was downloaded by 100000835139325 from CourseHero.com on 05-31-2022 03:33:55 GMT -05:00 https://www.coursehero.com/file/65199491/Bupropion-HCl-synthesis-lab-reportdocx/ Powered by TCPDF (www.tcpdf.org)
