Wednesday, May 31, 2006

Exp 013

To convert adrenaline to a catechol aldehyde using acid catalysis. How this fits into the synthesis of anti-malarials is described here.

Adrenaline (215 mg, 1.173 mmol) was added to a 100mL round bottom flask with glacial acetic acid (40mL) and water (4mL). The solution was refluxed 24 hours under nitrogen.

Took round bottome flask of sample 13E, and evaporated the 40mL of acetic down to 10mL. 2hr video 10hr video 24hr video

TLC results of what remained from vacuum pump show some movement in 1:1 methylene chloride methanol. Also in pure methanol.

Analyzing peaks and waiting for spinning to be fixed. Concentration of any product may have been too little however the number of scans was also insufficient. Next reaction will be more concentrated.

9:30) sample taken (13A), solution yellow
10:57) solution boiling with slight reflux, heat raised, solution still yellow, sample taken(13B)
11:20) reflux is insufficient, heat turned up to produce better reflux
14:56) sample taken(13C), reflux is better but slow, no changes in color
20:10) sample taken(13D), solution is still yellow, reflux is decent

solution did not change over night, sample taken(13E) reflux was still decent

Took C13 on Varian 300MHz NMR. Concentration wa approximately 20mg(combination of unreacted adrenaline and any product that formed)/1mL acetic acid

15:00)Vacuumed off the remaining acetic acid. A dark polymer like solid remained.
16:00)Scrapped a little off and dissolved it in 1-1.5mL methanol.
16:40)TLC in 1:1 methylene chloride hexanes showed nothing.
16:50)TLC Pure methylene chloride showed nothing.
17:00) 1:1 methylene chloride methanol produced some movement.
17:10) Pure methanol produced about the same result as the 1:1 methylene chloride in methanol.

Exp 012

To convert adrenaline to a catechol aldehyde using acid catalysis. How this fits into the synthesis of anti-malarials is described here.

Adrenaline (227 mg, 1.239 mmol) was added to a 100mL round bottom flask that holds a thermometer with concentrated sulfuric acid (80mL) . The solution was held at 70C for 24 hours under nitrogen.

Obtained HNMR but sulfuric acid was the main peak. Need C13 NMR but concentration is too low. Spinner on 300MHz NMR is not operating correctly. Sulfuric solution was diluted with 400mL of water. 2 x 150mL was taken out and one separated with methylene chloride and the other with benzene. TLC of the methylene chloride extraction revealed nothing as well as the benzene extraction.
2hr Video 10hr video 24hr video

No further tests have been done. Nothing else to report at this time.

9:30) t=0 sample taken, rheostat set at 51, starting temperature is 30C, solution is light brown
10:57) t=1hr 40min sample taken, temp from rheostat=51 is 61C, rheostat increased to 57, hood sash is fully open, solution is brown
11:18) temperature at 68C from rheostat=57, rheostat pushed to 59
12:15) temperature at 75C from rheostat=59, lowered rheostat to 55, solution is dark brown
15:10) temp=64 from rheostat=55, reset the rheostat set between 56-57, very dark solution, sample t=5.5 hrs
20:10) t=10.5hr sample taken, color same, temp=75C and hood sash was lowered and temp decreased to 68C, rheostat set to approx. 56

8:15) no change in color, sash remained at lowered position all night, rheostat at 56 and temperture at 72C

Wednesday, May 24, 2006

Exp 011

To convert adrenaline to a catechol aldehyde using acid catalysis. How this fits into the synthesis of anti-malarials is described here.

Adrenaline (302 mg, 1.653 mmol) was added to a 100mL round bottom flask with concentrated sulfuric acid (40mL) and a benzene layer (27mL+10mL). The solution was refluxed 24 hours under nitrogen.

The start of the reaction clearly showed two layers here.
After 40minutes there seemed to be only one phase. This video may be deceiving because there is a reflection on the round bottom flask giving the appearance of 2 layers.
A TLC of a small benzene/water extraction (benzene layer) after 24 hours showed little signs of anything UV active.

We would expect the catechol aldehyde to partition in the organic phase of a benzene/aqueous sulfuric acid mixture and be UV active when spotted on a TLC plate, but did not observe this even after 24 hours of reflux.
Here is paper on an experiment that used silica sulfuric acid and benzene to make benzene sulfonic acid. Chances are good that is what happened. Possibly the sulfuric acid concentration should be reduced or the concentration of adrenaline which can act like a soap between the benzene and acid layer.

Refluxing adrenaline in a mixture of benzene/sulfuric acid for 24 h did not produce the desired aldehyde.

1700hours The bubbler oil is brown from Exp 010 but the reaction starts and heat has been turned on. Took sample.
1740hours Where is the benzene layer? The volume is the same and there is only a small benzene layer. Took sample.
19:40)before leaving added 10mL more benzene. Sample taken.
9:40) Volume of solution was the same. No sample taken.
17:20) Heat turned off. Flask and solution were allowed to cool under nitrogen while water continued through the condenser.
18:00) Turned off water and nitrogen and put parafilm over flask.

Tuesday, May 23, 2006

Exp 010

To convert adrenaline to a catechol aldehyde using acid catalysis. How this fits into the synthesis of anti-malarials is described here.

Adrenaline (303 mg, 1.653 mmol) was added to a 100mL round bottom flask that had a spout for a thermometer then added concentrated sulfuric acid (40mL). The solution was heated to an uncertain temperature with a reflux condensor for 14 hours under nitrogen.

At some point during the night the stir plate stopped stirring and sulfuric vapors escaped through the the condenser and ended up in the oil for the nitrogen bubbling. As seen in the videos the thermometer did not actual reach the liquid layer and the reading it gave was off of fumes from the sulfuric acid.
Evening video Next morning video.
Reaction was stopped, water was added to solution. Tried to separate with methlyenechloride but the acid solution was an emulsion. A quick TLC revealed no UV absorption.

Unsure if sulfuric would still travel up the condenser if more stirring was provided. Benzene layer may be needed for concentrated sulfuric. The temperature was probably to high which would account for the color change in the bubbling oil.

Make sure thermometer is in contact with the solution next time.

19:50) Added sulfuric acid, and adrenaline to a 100mL r.b.f. with a spout for a thermometer. (Thermometer did not touch solution) Took sample t=0, left over night.
9:50) Stirrer stopped during the night and sulfuric escaped through the condensor and out the N2 needle. Heat turned off. Sample taken.

Friday, May 05, 2006

Exp 009

To convert adrenaline to a catechol aldehyde using acid catalysis. How this fits into the synthesis of anti-malarials is described here.

Adrenaline (112 mg, 0.665 mmol) was added to a 50mL round bottom flask with concentrated sulfuric acid (15mL) and benzene (15mL) and water (2mL). The solution was refluxed for 24 hours under nitrogen.

The bottom layer (sulfuric layer) turned from yellow to brown to black faster than Exp 008. Benzene layer remained colorless.
Spotting the benzene layer showed some UV activity however in 2:1 methylene chloride hexanes there seemed to be a very small movement.
The benzene layer at first gradually disappeared however this was fixed after witnessing the reflux condenser here when taking the first sample.
Start of reflux, sample 23hrs of reflux, not seen in other refluxes.

If the aldehyde formed in the benzene layer, which the slight movement on the TLC plate would suggest, in this before and after shot ,then the reaction is working. However the concentration is low and the movement can not be seen well. Any amines, including the adrenaline starting material, should remain in the acidic aqueous phase. The TLC plates were stained with Ninhydrin and it shows that there are no amines in the benzene layer. The samples that were spotted on the TLC plates had very little benzene in them for some reason. They are at the beginning of the reaction so it is assumed that the aldehyde does not form that rapidly. The problem with keeping the benzene layer was fixed by taping the condenser and increasing the nitrogen pressure.

The desired aldehyde may have been produced but there is still too little of it. Next try will be an increase in adrenaline of about 3 times this concentration.

13:30. Added all components to 50mL round bottom flask
13:55. Took sample t=0 and turned heat on
14:28. Reflux starts
15:28. Sample t=1hr taken
16:28. Sample t=2hr taken
21:10. Sample t=6.5hr taken, benzene layer depleting, 15mL more benzene added
9:45. Sample 19hr taken
12:00. Sample 21.5hrs taken
13:40. Sample 23 hours taken
14:30. Sample 24 hours taken, heat turned off, solution capped
TLC done in 1:1 methylene chloride - no change
TLC done in 2:1 methylene chloride - some movement
Added 20mL of DI water to round botttom flask and put into 125mL separation funnel
Separated out the acid layer and the benzene layer
Added 10mL more water to acid layer and put back into separation funnel
Added 20mL of benzene, separated and added benzene layers
Put acid layer back into separation funnel and added 30mL benzene
Separated, added benzene layers together and set acid layer aside
Rotovaped the combined benzene layers in 100mL round bottome flask ending with some acid layer still present because Magnesium sulfate was not added.
Took round bottome and added benzene approx. 80mL and 10mL of water, separated then added magnesium sulfate to benzene layer and filtered
Took round bottom flask with benzene and rotovaped ending with a little benzene still left over with a yellowish color.
Took round bottom flask that was rotovaped which still had some benzene and put it on a vacuum pump. Before doing so the weight of a 50mL round bottom flask was taken (33.86g), the contents of the 100mL r.b.f. was added along with 5mL of methylene chloride, the weight was taken again (40.35g). The flask was put on the vacuum pump and the methylenechloride and benzene were evaporated. The final weight was also taken (33.87g) giving an approximate 10mg of product. A Chromatotron will be done.
A Chromatotron was performed under nitrogen gas. 10mL of methylene chloride was added to the vacuumed sample and spotted first on a TLC plate and then added to the Chromatotron. A TLC plate was done in pure methylene chloride prior to the chromatotron and the same spot ran quickly suggesting that the same compound is present. The solvent used was 2:1 methylene chloride with hexanes. The bands formed and moved quickly under the force of the moving plate. Before first fraction After first fraction