Honors Organic Chemistry Lab

Dr. Deborah Lieberman Dr. Alan Pinhas Spring Semester 2013 Thursday 2:00 5:30

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

Importance of Oxazolidinone
Brad and Destiny

Importance of Oxazolidinone
Ligands for Metal Catalysts1 Protecting Groups1 Chiral Auxiliaries Pharmaceuticals

Chiral Auxiliaries
High Diastereoselectivity
Michael additions Alkylations Aldol condensations Cyclopropanations Diels-Alder

Soluble in Organic Solvents Removable under mild hydrolysis2

Pharmaceutical Significance
Antibacterial Activity Active against gram-positive pathogenic bacteria3
New class of synthetic antibacterial agents active against multiple-resistant gram-positive pathogen MRSA, Streptococci, Enterococci3

New mechanism for antibacterial activity

Inhibits bacterial translation at the initiation phase of protein synthesis Binds to 50s Ribosomal unit of bacteria3

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?

Amino Alcohol Formation

Sarah and Katie

Importance
Many amino alcohols are found in medications and biochemicals (such as -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

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

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

Mechanism

Theoretical Yield
2.28mL styrene oxide 0.0199 mol 2.18mL benzylamine
0.982g 1mL 1.052g 1mL

1 mol 120.16g

1 mol 107.17g

= 0.0199 mol

0.0199 mol amino alcohol

227.32g 1 mol

= 4.52g

Ether removes the 20% product that attacks at most substituted carbon atom 4.52g 0.80 = 3.62g Theoretical Yield

Percent Yields

Group Sarah and Katie Alexandra and Rachel Ellen and Joe

Grams of amino alcohol 1.2g .877g 1.6g

Percent yield 33% 24% 44%

Sean and Robert

2.003g

55%

H-NMR

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

Mechanism of Aziridine Formation

Rachel and Alexandra

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

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

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

Mechanism of Oxazolidinone Reaction

Thi and Tri

Synthesis Mechanism

Mechanism Overview

Mechanism Overview, continued

Mechanism 1: Intermediate Reacts with Aziridine

Mechanism 1, continued

Mechanism 2: Intermediate Reacts with Intermediate

Mechanism 2, continued

Reaction Results Overview

Nikki and Allison

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

Temperature and Packing

Yields were generally highest when vial was packed with CO2

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

Catalysts and Shaking

Yields were higher with shaking Yields were generally higher with catalysts
LiI and NH4I did not vary significantly in percent yield results More reactions were run with Lithium Iodide than with Ammonium Iodide

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

Catalyst Comparison
Ellen and Joe

Catalyst Analysis
NH4I

Only 3 trials for NH4I NH4I most successful catalyst, based on limited data

LiI
High yields with LiI and packed CO2 and ether Necessary for reacting with benzaldehyde, based on one trial Need to run reaction with LiI, packed CO2, and no ether Determine if high yields are due to packed CO2 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

Average Percent Yields: Reaction Condition Dependence

Average Percent Yields: Temperature Dependence

Room temperature appears to be best Vary environment temperature for future LiI reactions to gather more data

Application and Results of Stereoisomerism

Robert and Sean

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

R-Styrene Oxide
%Yield Catalyst No Catalyst 50/50 Aziridine 68.3% 34.1% R-Only Aziridine 88.3% 75.5%

Conclusion:
Strict stereoisomerism appeared to have no negative effect on the yield of Oxazolidinone

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

Stereoisomerism, continued
O
HO OH

*
NH2
N H
+

*
N H

HO

OH

*
N H
+

*
N H

O CO2 N N O

* * - Denotes chiral center

Specific Results

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 80C

All reactions had excess CO2

All reactions had some Aziridine left over

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 CO2
Temperature
Freezer Room Temp 80C

Reaction Time
1 Week 1 Week 1 Week

Mass Total Product 27 mg 32 mg 58 mg

% Oxazolidinone 98% 96% 29%

% Aziridine
<1% <2% >60%

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)

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.