Honors Organic Chemistry Lab:Developing an aziridine

Winter Quarter 2012Ren AriizumiKristine Bauer-NilsenAllison BergmannKara GuisingerNicholas HerrmannHirsch MataniDevin Metzger

Leslie PaytonBradley RockwellErica RossDaniel RuterMargaret SfiligojStephanie VenturaLindsay Webb

The Basics

• Many types of aziridine• Basic Structure: One amine group + two

methylene groups = three-membered heterocycle

• C2H5N• Bond angles ~60° (normal

hydrocarbon has bond angle of 109.5°)

Uses• For the purposes of the Honors Lab, aziridine

used in synthesis of oxazolidinones• Oxazolidinone is a synthetic antimicrobial agent—inhibits

bacterial protein synthesis• As more bacteria become resistant to antibiotics,

oxazolidinones remain effective against many antibiotic-resistant bacteria (i.e. Staphylococcus aureus and Streptococcus pneumoniae)

• Used as last resort antibiotic• Newer treatment—long-term effects not yet known• Very expensive!• Linezolid is first oxazolidinone

approved for clinical use—active against most Gram-positive bacteria

Aziridine Synthesis

1) Styrene oxide + Benzylamine → Amino Alcohol

2) Amino Alcohol + Triphenyl phosphine***/Trimethyl phosphite/Triethyl phosphite + Bromine + Triethylamine (in Acetonitrile solvent) → Aziridine

***Do not use triphenyl phosphine, as isolating product and removing byproduct is extremely difficult

Why are we doing this?

• Looking for most efficient synthesis—fastest with most product

• Looking to develop purest product• Looking to find alternative methods of

synthesis

Experiment 1: trimethyl vs. triethyl phosphite

Trimethyl phosphite Triethyl phosphite

We compared use of these two compounds to determine which compound gives a higher yield of aziridine product

Compound Price/100 mL*Trimethyl phosphite Sigma-Aldrich catalog #92730

$52.80

Triethyl phosphite Sigma-Aldrich catalog #T61204

$19.10

Cost of Reagents

Mass spec at 17:45

Aziridine

Use of Trimethyl Phosphite

Use of Triethyl Phosphite

Aziridine

Mass spec at 17:30

Use of Triethyl Phosphite

Unknown product

Mass spec at 17:45

No aziridine

Molecular Weight of known compounds

Starting MaterialsBenzylamine 107Styrene oxide 120

Reagents/solventsAmino alcohol 227Trimethyl phosphite 124Triethyl phosphite 166Triethyl amine 101Acetonitrile 41Bromine (Br2) 160

ProductsAziridine 208??? 244

Conclusions

• Use of triethyl phosphite gives significant amount of unknown product• Unable to confidently identify molecular composition of

unknown product (mw: 244) based on starting materials and reagents

• Regardless of efficiency, triethyl phosphite is not a viable option

• Future experiments should only use trimethyl phosphite

Experiment 2: Heat and Duration

• Heat vs. no heat– We compared groups that heated vs. those that

kept the reaction at room temperature.• Reaction duration– We analyzed the effect of extending the duration

of the reaction.

Procedure1. Same amino alcohol and procedure– Until after triethylamine added

2. Let stir for 30 min.– After triethylamine added

3. Heat/no heat depending on group– Heat for 45 min. at 40-45°C

4. Let sit depending on group5. Continue experiment on group specific day– Monday or Tuesday

• One group heated overnight and continued experiment the next day

Friday Monday Tuesday

Overnight heating

6% - -

Heat 45 min. 45°C

7% 10% 26%

No Heat 6% 9% 5%

Results – Percent Yield

45% Yield

Amino AlcoholAziridine

26% Yield

AziridineAmino Alcohol

Conclusions

• Heating the reactions increased percent yield.• Longer reaction duration of time spent mixing

at room temperature increased percent yield.• Most yield was from amino alcohol– Exception of one group that had high impurities

• Decided to control the variable of impurities caused by different amino alcohols.

Experiment 1: Use Trimethyl Phosphate

Further Control: Used Same Amino Alcohol for all TrialsWhy: -Impurities

-Difference in exact amounts of reagents used and procedure could affect efficacy of amino alcohol in reaction

Experiment 2: Stirring for longer periods results in higher Aziridine yield

Control: Stir all trials for 7 days

Applying What We Learned from Previous Experiments…

Experiment 2: Heating reaction results in higher Aziridine yield

Proposed Treatments…Heat for 45 minutes at 45˚

Heat until Monday at 45˚ (4 days; 96 hours)Heat until Wednesday at 45˚ (6 days; 144 hours)

Reflux overnight at 80˚ (24 hours)

Experiment 3: Heat Duration and Intensity

Hypotheses: •Longer heating duration would result in higher Aziridine yield •In comparison to Experiment 2 results: longer stirring duration for all trials would result in higher Aziridine yield •Reflux would result in highest Aziridine yield

Negative:Loss of reproducibility

Positive:More variation possibly resulting in finding a high yielding method

Actual TreatmentsHeated for 45 minutes at 45˚

Heated up to 100˚, then 80˚ overnightHeated up to 80˚, then 60˚ overnight

Heated to 65˚, then cooled to room temperature over 4 daysHeated to 45˚, then cooled to room temperature over 4 days

Heated to 45˚, then cooled to 30˚ for 4 days, then heated to 40˚ for 2 daysHeated to 45˚, then cooled to 32˚ for 7 days

To Do:Acquire method to accurately heat at desired temperature

Results

Treatments % Yield of

Aziridine

Heated for 45 minutes at 45˚ 3%Heated up to 100˚, then 80˚ overnight 10%Heated up to 80˚, then 60˚ overnight 31%

Heated to 65˚, then cooled to room temperature over 4 days 13%Heated to 45˚, then cooled to room temperature over 4 days

Heated to 45˚, then cooled to 30˚ for 4 days, then heated to 40˚ for 2 days

3%

Heated to 45˚, then cooled to 32˚ for 7 days -

Hypothesis: •Longer heating duration would result in higher Aziridine yield

Conclusion: Inconclusive

Treatments % Yield

Heated for 45 minutes at 45˚ 3%Heated to 65˚, then cooled to room

temperature over 4 days13%

Heated to 45˚, then cooled to room temperature over 4 days

6%

Heated to 45˚, then cooled to 30˚ for 4 days, then heated to 40˚ for 2 days

3%

Heated to 45˚, then cooled to 32˚ for 7 days

-

Expected

Highest Yield

Hypothesis:•In comparison to Experiment 2 results: longer stirring duration for all trials would result in higher Aziridine yield

Conclusion: Inconclusive

Experiment 2 Overnight 4 Days 5 Days

Heat 45 min. 45°C 7% 10% 26%

Experiment 3 7 DaysHeated for 45 minutes at 45˚C 3%

Observed Highest Yield

Possible Explanations:•Variable amino alcohol led to high yield in experiment 2 (5 days)•Human Error

Hypothesis:•Reflux would result in highest Aziridine yield

Conclusions: Plausible

Treatments % Yield of Aziridine

Heated for 45 minutes at 45˚ 3%Heated to 65˚, then cooled to room

temperature over 4 days13%

Heated to 45˚, then cooled to room temperature over 4 days

6%

Heated to 45˚, then cooled to 30˚ for 4 days, then heated to 40˚ for 2 days

3%

Heated up to 100˚, then 80˚ overnight 10%Heated up to 80˚, then 60˚ overnight 31%

Expected

Highest Yield

Final Conclusions

• Our goal was to synthesize the purest aziridine. • What worked best:– Trimethyl phosphite works better than triethyl

phosphite because triethyl phosphite resulted in an unknown impurity

– Heating for 45 minutes and letting stir for 4.5 days.• Letting the reaction sit longer seems to improve the

percent yield the most– Letting the solution reflux overnight led to the best

percent yields

Future Work

Next quarter we hope to: • Replicate the experiment that gave the purest

aziridine• Make oxazolidinone using CO2 with the purest

aziridine– Applications: antibiotics, starting material for

other products

Oxazolidinone Synthesis• One possible way of synthesis from aziridine

Phung, C., Ulrich, R. M., Tighe, N. T. G., Lieberman, D. L., Pinhas, A. R. (2011). The solvent-free and catalyst-free conversion of an aziridine to an

oxazolidinone using only carbon dioxide. Green Chemistry, 2011, 3224- 3229. doi: 10.1039/C1GC15850C .

Future Work continued

Other goals for next quarter:• Make other heterocycles using a different

electrophile than carbon dioxide, such as an aldehyde or an imine

• Find out if we can develop heterocycles on the bench or with high speed ball milling−do we get the same regiochemistry and

stereochemistry by the two different methods?