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 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
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)-1-phenylethanol
• Forms new chiral center!
Mechanism
Theoretical Yield
• 2.28mL styrene oxide ×
• 2.18mL benzylamine ×
1.052g
1 mol
×
1mL
120.16g
0.982g
1 mol
×
1mL
107.17g
• 0.0199 mol amino alcohol ×
227.32g
1 mol
= 0.0199 mol
= 0.0199 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
Grams of amino alcohol
Percent yield
Sarah and Katie
1.2g
33%
Alexandra and Rachel
.877g
24%
Ellen and Joe
1.6g
44%
2.003g
55%
Sean and Robert
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
•
Conclusion:
• Strict stereoisomerism appeared to
have no negative effect on the
yield of Oxazolidinone
*
R-Styrene Oxide
%Yield
50/50
Aziridine
R-Only
Aziridine
Catalyst
68.3%
88.3%
No Catalyst
34.1%
75.5%
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
HO
O
*
HO
*
+
NH2
*
*
N
H
*
N
H
+
N
H
OH
N
H
+
OH
N
*
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 80°C
• 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
Reaction Time
Mass Total
Product
% Oxazolidinone
% Aziridine
Freezer
1 Week
27 mg
98%
<1%
Room Temp
1 Week
32 mg
96%
<2%
80°C
1 Week
58 mg
29%
>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.