1. Honors Organic Chemistry Lab Dr. Deborah Lieberman Dr. Alan Pinhas Spring Semester 2013 Thursday 2:00 – 5:30

2. Table of Contents Importance of Oxazolidinone Formation of Amino Alcohol Mechanism of Aziridine Formation Mechanism of Oxazolidinone Reaction Reaction Results Overview Catalyst Comparison Applications and Effects of Stereoisomerism Specific Conditions, Results, etc. References

3. Importance of Oxazolidinone Brad and Destiny

4. Importance of Oxazolidinone Ligands for Metal Catalysts 1 Protecting Groups 1 Chiral Auxiliaries Pharmaceuticals

5. Chiral Auxiliaries High Diastereoselectivity Michael additions Alkylations Aldol condensations Cyclopropanations Diels-Alder Soluble in Organic Solvents Removable under mild hydrolysis 2

6. Pharmaceutical Significance Antibacterial Activity Active against gram-positive pathogenic bacteria 3 New class of synthetic antibacterial agents active against multiple-resistant gram-positive pathogen MRSA, Streptococci, Enterococci 3 New mechanism for antibacterial activity Inhibits bacterial translation at the initiation phase of protein synthesis Binds to 50s Ribosomal unit of bacteria 3

7. Why Study the Synthesis? By understanding the reaction, optimal synthetic efficiency can be achieved Areas for improved understanding: What is the best way to synthesize the starting materials? Is Carbon Dioxide the only electrophile capable of forming the product? Which physical and chemical conditions work best? Best yield, highest rate, cheapest conditions, etc. Can regiochemistry and stereochemistry be controlled?

8. Amino Alcohol Formation Sarah and Katie

9. Importance Many amino alcohols are found in medications and biochemicals (such as β -blockers – treatment of cardiac arrhythmias – and biological buffers) Used in: Water treatment to neutralize amines Personal care and cosmetic products Paints and coatings Corrosion protection and emulsion stability for metal working Important in formation of Aziridine

10. Procedure Combine 2.28mL styrene oxide with 2.18 mL benzylamine Stir for 72 hours Add ether Pipette ether off after 24 hours Product is 2-(benzylamino)-1-phenylethanol

11. 2-(benzylamino)-1-phenylethanol Forms new chiral center!

12. Mechanism

13. Theoretical Yield

14. Percent Yields GroupGrams of amino alcoholPercent yield Sarah and Katie1.2g33% Alexandra and Rachel.877g24% Ellen and Joe1.6g44% Sean and Robert2.003g55%

15. H-NMR

16. Conclusion Poor percent yields possibly due to: Taking off some of major isomer with ether Inexact 4-1 ratio of isomers

17. Mechanism of Aziridine Formation Rachel and Alexandra

18. Mechanism Reaction: Acetonitrile reacts with triphenylphosphonium dibromide in the presence of triethylamine to form Aziridine Acetonitrile and hexane as solvents

19. Synthesis of Aziridine Procedure: Add 3.87g of triphenylphosphonium dibromide to 19 mL acetonitrile in round bottom Cool in ice bath for 10 minutes Slowly add 2.0g amino alcohol Dissolve 3.67mL triethylamine in 5.3mL acetonitrile and add dropwise to the reaction Stir reaction for 30-60 minutes

20. Synthesis of Aziridine, continued Procedure, continued: Gravity filter off the triethylamine hydrobromide Concentrate the solution using rotary evaporation Treat the residue with 8mL of hexane Filter the solution to remove triphenylphosphine oxide Evaporate the solution to obtain Aziridine

21. Mechanism of Oxazolidinone Reaction Thi and Tri

22. Synthesis Mechanism

23. Mechanism Overview

24. Mechanism Overview, continued

25. Mechanism 1: Intermediate Reacts with Aziridine

26. Mechanism 1, continued

27. Mechanism 2: Intermediate Reacts with Intermediate

28. Mechanism 2, continued

29. Reaction Results Overview Nikki and Allison

30. Overview of Results Seven groups ran separate experiments throughout the semester Different catalysts, temperatures, and external conditions were applied to test differences in product yields and results Teams calculated percent yields using the GC-Mass Spec A mass spec peak at 253 suggests the presence of Oxazolidinone All GC peaks were integrated The area of a GC peak corresponding to Oxazolidinone product was divided by the total area of all curves in order to account for any starting material still present

31. Temperature and Packing Yields were generally highest when vial was packed with CO 2 Yields were highest when the reaction was run at room temperature Only four reactions were run at lower or higher temperatures More research could be done regarding temperature to further verify these results

32. Catalysts and Shaking Yields were higher with shaking Yields were generally higher with catalysts LiI and NH 4 I did not vary significantly in percent yield results More reactions were run with Lithium Iodide than with Ammonium Iodide

33. Ether, Pressure, & Benzaldehyde Not using ether did not significantly lower yields Pressure was determined to be present if the steel reaction vial hissed when opened, and average yields were actually higher when pressure was not present Two reactions were run with benzaldehyde, neither of which yielded any Oxazolidinone

34. Catalyst Comparison Ellen and Joe

35. Catalyst Analysis NH 4 I Only 3 trials for NH 4 I NH 4 I most successful catalyst, based on limited data LiI High yields with LiI and packed CO 2 and ether Necessary for reacting with benzaldehyde, based on one trial Need to run reaction with LiI, packed CO 2, and no ether Determine if high yields are due to packed CO 2 or ether No catalyst Reaction is successful without catalyst Ether is beneficial to reaction, but not necessary Shaking is beneficial to reaction, but not necessary

36. Average Percent Yields: Reaction Condition Dependence

37. Average Percent Yields: Temperature Dependence Room temperature appears to be best Vary environment temperature for future LiI reactions to gather more data

38. Application and Results of Stereoisomerism Robert and Sean

39. Stereoisomerism Procedure: Attempted to synthesize Oxazolidinone twice using Aziridine that had been made using amino alcohol produced from R-only styrene oxide One attempt was made with a lithium iodide catalyst, one without Compared to respective controls with standard 50/50 Aziridine Conclusion: Strict stereoisomerism appeared to have no negative effect on the yield of Oxazolidinone R-Styrene Oxide * %Yield 50/50 Aziridine R-Only Aziridine Catalyst68.3%88.3% No Catalyst34.1%75.5%

40. Stereoisomerism, continued Further Studies: By using a polarimeter on the starting materials, intermediates, and final product, the stereochemistry of each step can be revealed yielding useful information that could be used to predict the mechanism Understanding the mechanism would allow the procedure to be adjusted to maximize yield in each step

41. Stereoisomerism, continued * - Denotes chiral center * ** ** * * *

42. Specific Results

43. Notable Results: Brad &Destiny Warm temperatures appeared to have a negative impact on reaction High yields in freezer and at room temperature 29% yield at 80 °C All reactions had excess CO 2 All reactions had some Aziridine left over

44. Notable Results: Brad &Destiny, continued Almost all of the Aziridine was converted to product at room temperature and in the freezer When heated, less Aziridine reacted with excess CO 2 TemperatureReaction Time Mass Total Product % Oxazolidinone% Aziridine Freezer1 Week27 mg98%<1% Room Temp1 Week32 mg96%<2% 80°C1 Week58 mg29%>60%

45. Notable Results: Sarah & Katie Shaking produced much higher yields Without shaking, Oxazolidinone took longer to come off in mass spec ~5 minutes longer Potential correlation between low percent yield and longer retention time Ether seemed to have no effect on yield (with shaking)

46. References 1- Wallace, Justin, Deborah Lieberman, Mathew Hancock, and Allan Pinhas. "Conversion of an Aziridine to an Oxazolidinone Using a Salt and Carbon Dioxide in Water." Journal of Chemical Education. 2- "Oxazolidinone Chiral Auxiliaries." Sigma-Aldrich. 3- Neha, Pandit, Rajeev Singla, and Birenda Shrivastava. "Current Updates on Oxazolidinone and Its Significance." Current Updates on Oxazolidinone and Its Significance. 4-"Amino Alcohols." Dow Chemical Corporate Website., 2013. Web. 14 Apr. 2013.