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Topic: Synthesis of isotopically labeled octahydrophenazine  (Read 619 times)

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Offline BL1996

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Synthesis of isotopically labeled octahydrophenazine
« on: September 07, 2019, 04:35:22 AM »
Hello everyone! I am a biotech student but for some reasons I am doing an internship in a chemical companyz. As one of my tasks I had to design a synthesis for isotopically labeled octahydrophenazine using relatively cheap labeled precursor, easy procedure without using any “fancy” equipment and of course good yelds. I did some research and I came up with a 5 step route starting with deuterated cyclohexane. I had shown this to my supervisor, he looked at it for like a minute and said – "Ok, it is fine." Next day he told me he had ordered 1g of deuterated cyclohexane lol. I came here for some help because I feel like my supervisor doesn’t care about my success or failure in synthesizing this compound and also seems busy and don’t pay much attention when I have some questions. Our conversations usually took like 2minutes. But I care about this little project and want to get it done so here I am =]

The synthesis I designed goes like this

1) Selective chlorination of cyclohexane with cobalt(II) porphiryn complex

Source Khanna, V., Tamilselvan, P., Jeet Singh Kalra, S., & Iqbal, J. (1994). Cobalt(II)-porphyrin catalyzed selective functionalization of alkanes with sulfurylchloride: A remarkable substituent effect. Tetrahedron Letters, 35(32), 5935–5938. https://doi.org/10.1016/S0040-4039(00)78223-2

2) Elimination reaction to get cyclohexene

3) Selective oxidation to cyclohexanone

Source https://www.designer-drug.com/pte/12.162.180.114/dcd/chemist...

4) Bromination with NBS to 2-bromocyclohexanone

As described in this paper Zhang, G., Wang, F., Du, J., Qu, H., Ma, X., Wei, M., & Wang, C. (n.d.). Supporting Information Towards the Total Synthesis of Palhinine A : Expedient Assembly of Multifunctionalized Isotwistane Ring System with Contiguous Quaternary Stereocenters.

5) Condensation with ammonia to octahydrophenazine using microvawe or just heating it in a flask for some time

Utsukihara, T., Nakamura, H., Watanabe, M., & Horiuchi, C. A. (2006). Microwave-assisted synthesis of a -hydroxy ketone and a -diketone and pyrazine derivatives from a -halo and a , a 0 -dibromo ketone, 47, 9359–9364. https://doi.org/10.1016/j.tetlet.2006.10.087

I am testing this procedure using normal reagents and I failed at step 1. I used a 3,5ml of cyclohexane, 10ml of benzene, 5ml of sulfuryl chloride and 34mg of porphiryn. I had a problem with a temperature sensor so the temperature so for some time was too high(110°C). I didn't get any mono or disubstituted halogenes. After about 15hrs of refluxing the mixture at 85 I transfered it to another flask suitable to distillation in small scale. In the first(refluxing flask) remained a lot of black tarry solid which was unexpected. The liquid in a second flask had dark brow/oragne colour which makes me think that due to overheating porphiryn decomposed but I found some paper and If I understood it correctly it should be stable at this temperature
https://www.researchgate.net/publication/260261591_Spectral_and_thermal_investigations_of_porphyrin_and_phthalocyanine_nanomaterials

Another thing that may cause the failiure may be the porphirin itself. Some time ago my supervisor gave me a mini jar with label "tetrakis(4-methoxyphenyl)porphyrin". It is purple compact pieces but not shiny, I forgot to take picture.
The procedure he told me to make cobalt complex from it is:
"Dissolve (200mg) porphiryn in chloroform
Dissolve (1g) cobalt acetate in methanol
Mix it and add about 5g of sodium carbonate as a base to get protons from porphiryn
Heat under reflux for 2 to 4h
Filtrate and evaporate solvents under reduced pressure"

I am not sure if using sodium carbonate is really necessary because
1) It poorly disolves in that solvents
2) I found a paper describing the synthesis of porphpiryn and no such thing was used
https://www.tandfonline.com/doi/pdf/10.1080/00397910802574617
3) I think that it reacts with cobalt acetate
(CH3COO)2Co+Na2CO3 -> CoCO3 + 2CH3COONa
I checked cobalt carbonate in google images and it looks so simillar to some of the solid that stays on the filter after filtration of reaction mixture that I am almost sure it does react and really no cobalt gets built into porphiryn.
What do you think? Should sodium carbonate be used in this reaction or is he just trolling me?
I was promised to do an UV-VIS spectra to confirm if the product is really the porphiryn Co complex but it was not done. Instead he looked at the small purple shiny crystals I got after the reaction and said "Ok, It looks fine, this is it".

Also I have a quick question about elimination reaction. I couldn't find conditions for it but i think that dissolving some base (I have KOH, NaOH, t-BuONa) in propanole(because it has higher boiling point than cyclohexene i want to get) and refluxing it for couple hours is the right approach to it.

Besides what do you guys think about this synthesis route? Can I improve it to get the desired product in faster and more efficient way starting with cyclohexane? Someone on other forum suggested using TsNBr2 to convert cyclohexene to bromocyclohexanone in one step but I would have to make it from p-TsOH and it seems like a lot of work.

PS English isn't my native language so sorry for any grammar mistakes ;p

Offline rolnor

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #1 on: September 07, 2019, 09:37:36 AM »
I think your route is interesting, I agree that the cobaltcomplex is probably bad.
It should be possible to find procedure for the emimination, the isolation of the product is critical, the cyclohexene is very volatile and thats an issue. Distillation on this small scale requires special equipment.
You can buy the cyclohexanone-d10 but thats maybe to expensive?
https://cdnisotopes.com/nf/d-0571
I dont know how much deutaration you need, when you make the cyclohexanone you will get hydrogen in your molecule?
Step 3 reference is not available when I click on it?

Offline BL1996

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #2 on: September 07, 2019, 12:53:06 PM »
Now the link should work
https://www.designer-drug.com/pte/12.162.180.114/dcd/chemistry/wacker.improvement.html
I will be using cyclohexane-d12. I was told that labeled octahydrophenazine will be used as internal standard for GC to determine "normal" octahydrophenazine concentration in some samples. The more difference in molar mass in final compound the better.
I know that I will get one deuterium atom replaced with hydrogen after making cyclohexanone and I might lose another one during bromination but I don't think that's a problem.
I have some equipment for small scale preparations, something like this
https://www.chemistry.mcmaster.ca/~chem2o6/labmanual/microscale/ms-dist1.jpg

You're saying that cyclohexene is very volatile so maybe setting the apparatus just like in the picture above and heating the mixture to the boiling point of cyclohexene is the best way to handle this elimination? The produced cyclohexene should be continuosly removed from the mixture thus enhancing the yeild right?

Offline rolnor

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #3 on: September 07, 2019, 01:20:58 PM »
There is a big risc that you get solvent mixed with the cyclohexene even with this apparatus. If you use t-BuOK in DMSO for the oxidation you get a big diffirence in boilingpoint. You could go from the chloride to the alcohol via for example the benzoic ester, this can be made if you treat the chloride with potassium benzoate in DMF with catalytic sodium iodide I think. This benzoic ester has UV-absorbance and can be purified on silica-gel. The cyclohexanol is then obtained through reaction with 1eq. piperidine, this gives you benzoylpiperidine and the cyclohexanol and these have very different boilingpoint. The cyclohexanol is easy to oxidize to the ketone with Dess Martin. I think in general the big problem with this procedure is the volatile nature of the cyclohexanol and the cyclohexanone, you will most certainly save both money, effort and time if you buy the cyclohexanone-d10.
« Last Edit: September 07, 2019, 01:52:22 PM by rolnor »

Offline BL1996

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #4 on: September 07, 2019, 01:51:25 PM »
Edit:
Ok, now I see the next part of your post. I am affraid that buying cyclohexane-d10 is not possible. I am just an intern that noone cares about lol. To make long story as short as possible - I was given this synthesis task because they thought I'll back off and give up because it will be to hard for me. But I didn't and came up with that 5 step route so they let me work on this project but I don't get much help or any budget. So buying anything is not an option. I have to use the materials they have and they don't have much really. For example I had to make NBS on my own, the sulfuryl chloride was "smuggled" from an unknown source to the lab after like two weeks of asking my supervisor for it.

I have a DMSO and t-BuOK so I'll give it a try, thanks! Unfortunately they don't have the DMP and I think DMF as well but I have to check.
« Last Edit: September 07, 2019, 02:41:01 PM by BL1996 »

Offline kriggy

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #5 on: September 07, 2019, 04:05:46 PM »
I dont know what are your exact requirements of isotopic labeling, by FAR the simples method is to start with ocathydrophenazine, dissolve it in deuterated water, add 10-20 mass% of Pd/C and heat it overnight in pressure tube at 160°C under 1atm of hydrogen (you bubble hydrogen through the solution for a while before you start heating it). This should selectively exchange all your protons for deuteriums. The exchange might not be 100%, im not sure if its a big problem for the application or not but I suppose as long as you get at least 2 and more D atoms incorporated you are fine.

See:
Sajiki, H., Aoki, F., Esaki, H., Maegawa, T., & Hirota, K. (2004). Efficient C-H/C-D exchange reaction on the alkyl side chain of aromatic compounds using heterogeneous Pd/C in D2O. Organic Letters, 6(9), 1485–1487. https://doi.org/10.1021/ol0496374

« Last Edit: September 07, 2019, 04:16:33 PM by kriggy »

Offline BL1996

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #6 on: September 07, 2019, 06:38:00 PM »
I feel so stupid right now. I haven't even thought of that kind of approach. Thank you very much for enlightening me ;D I'll show this paper to my supervisor on monday and hopefully the labeled octahydrophenazine will be ready by the end of next week.

Offline rolnor

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #7 on: September 08, 2019, 03:18:25 AM »
Nice kriggy!

Offline kriggy

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #8 on: September 11, 2019, 06:49:25 PM »
I feel so stupid right now. I haven't even thought of that kind of approach. Thank you very much for enlightening me ;D I'll show this paper to my supervisor on monday and hopefully the labeled octahydrophenazine will be ready by the end of next week.

Haha dont feel, there is so many stuff that you cant possibly know it all, thats why you/we come here :)

just be carefull, use autoclave for it. It gets quite pressurized at 160°C.

Offline hypervalent_iodine

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #9 on: September 11, 2019, 07:35:23 PM »
I feel so stupid right now. I haven't even thought of that kind of approach. Thank you very much for enlightening me ;D I'll show this paper to my supervisor on monday and hopefully the labeled octahydrophenazine will be ready by the end of next week.

Haha dont feel, there is so many stuff that you cant possibly know it all, thats why you/we come here :)

just be carefull, use autoclave for it. It gets quite pressurized at 160°C.

Sometimes you get so wrapped up in one idea you forget to even consider other, often better solutions. Happens to the best of us.

Offline wildfyr

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #10 on: September 12, 2019, 02:46:44 PM »
Really excellent find Kriggy! I'll keep this one my back pocket for the day I need to make some "fancy" deuterated compound. Sure beats a 5 step synthesis with an expensive and volatile starting material!

Offline Corribus

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #11 on: September 12, 2019, 04:28:11 PM »
Interesting. You could probably do it conveniently using a pressurized microwave digester.
What men are poets who can speak of Jupiter if he were like a man, but if he is an immense spinning sphere of methane and ammonia must be silent?  - Richard P. Feynman


Offline Enthalpy

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #13 on: September 14, 2019, 04:29:28 PM »
Kriggy reported a simple step to redistribute hydrogen and deuterium between a target compound and a source of deuterium. This step looks perfect to bring a few atoms of deuterium to the target.

If someone wants a high proportion of deuterium on the target compound, this single step becomes inefficient. To my understanding, Pd/C plus heat and pressure only helps H and D to move between the molecules, but brings no selectivity, so at best, the target gets the same proportion of D as the source has at the end of the step. For instance, 98% D at the target lets exploit a big excess of source from <100% to >98% only, huge waste.

Though, the simple redistribution of H and D can produce a highly deuteriated target and use efficiently the source. I suggest (and may not be the first) to have several redistribution steps and circulate the target and the source in opposite directions, as in a heat exchanger.

There would probably be more than the sketched four steps. Or rather, the process would be continuous, with one reactor and slow permanent flows, possibly in different phases. Yes, this fits an industrial process better than a lab.

Marc Schaefer, aka Enthalpy

Offline rolnor

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Re: Synthesis of isotopically labeled octahydrophenazine
« Reply #14 on: September 15, 2019, 06:44:05 AM »
But the D2O is in very lage excess enthalpy? Have you looked in the paper?

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