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Author: Subject: On The Synthesis of Nicotine
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[*] posted on 5-10-2022 at 14:18
On The Synthesis of Nicotine


Greetings !!
So i'm working on the Synthesis of Nicotine, the idea is to make it so that it's reasonably economic compared to the extraction of nicotine from tobacco, considering the tobacco accessible is less than 3% Nicotine Content.

My pathway is the next:
NICOTINA SINTETICA  [Esquema].jpg - 524kB
I think is reasonable, what do you Think ? :).

NOTE: The idea is to make it from bought 3-Cl-Pyridine and N-Methyl Proline

Some Report: Yield for Hoffman Reaction is: 45.4% and for Sandmeyer 21,27% for First try. The Eschweiler-Clarke reaction on Proline does not seems to want to work.
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Mateo_swe
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[*] posted on 5-10-2022 at 15:49


The extraction from tobacco must be much more economic.

For example, the pure nicotine used in commercial "tobacco free" white snuff is first extracted from tobacco plant, purified and then added to the synthetic bags to make the tobacco free white snuff.
They do this to avoid the tax on tobacco products.
They would sure synthesize the nicotine if it would have been cheaper.

But it sounds like a fun and interesting project.
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AvBaeyer
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[*] posted on 5-10-2022 at 18:33


Steps I and II seem ok in terms of potential success. I do not accept step III as a highly probable reaction sequence. Can you provide additional detail and references which you believe support the reaction as proposed? Even if step III succeeded as written, the nicotine would be racemic whereas natural nicotine is chiral.

AvB
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[*] posted on 6-10-2022 at 00:20


While waiting for busses, I have wondered how much nicotine could be extracted from cigarette ends.
It's difficult to be cheaper than "free".
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[*] posted on 6-10-2022 at 01:40


Hi Guys :)

NICOTINE FROM TOBACCO
I did actually tried extraction of Nicotine from tobacco, using steam distillation, acid-base extraction with petroleum ether solvent, but my yield was really bad and variable.So i started to think on synthetic nicotine.
Economically speaking, synthetic nicotine for the non industrial like me, is cheaper. I did try to find tobacco with high nicotine content [These would have made a difference] but had no luck

The idea was that Nicotine seems really similar to a Pyridine and a proline, just bonded :) So ... i thought of the pathway presented above

The Final Decarboxylative coupling is a reaction i didn't know about. Here is a paper with examples. "Decarboxylative coupling reactions: a modern strategy for C–C-bond
formationw" DOI: 10.1039/c1cs15093f
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Tsjerk
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[*] posted on 6-10-2022 at 03:41


Did you basify the nicotine when steam distilling it?
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[*] posted on 6-10-2022 at 05:14


Pretty sure that the reaction of proline and formaldehyde is giving 2,3,4,5-tetrahydropyrrolo[1,2-c]oxazol-6-one, i.e. ring closure to an inert hemiaminal. You may need to esterify proline first.



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[*] posted on 6-10-2022 at 09:01


Yes, i did bisify when steam distilling the nicotine, and even try Acid-Base extraction, there was just not much nicotine in it, and a lot of junk.

In regards to the proline step, i think i will try the methylation with methyl iodide at some point, and esterifing it seams possible. I will report back :)
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[*] posted on 6-10-2022 at 15:20


Chem Science -

Thanks for the reference helping justify your step III. Have fun with the synthesis attempt. I look forward to a report.

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[*] posted on 6-10-2022 at 17:09


Speaking of the price difference between natural and manufactured. We made a synthetic cholesterol at our company, the route is like 13 steps, it costs $$$ for the final product. They use it in vaccines for various purposes and they need to be able to certify that the final product is not of animal origin.



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[*] posted on 6-10-2022 at 19:13


Thank's AvB :) Yes yes these is an Ongoing Project and there will be reports :D
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[*] posted on 7-10-2022 at 08:16


Quote: Originally posted by Chem Science  
Yes, i did bisify when steam distilling the nicotine, and even try Acid-Base extraction, there was just not much nicotine in it, and a lot of junk.

In regards to the proline step, i think i will try the methylation with methyl iodide at some point, and esterifing it seams possible. I will report back :)

With methyl iodide it's very possible to over-methylate it, and end up with a quaternary ammonium salt.
It may be worthwhile making that step a reductive amination instead, with sodium cyanoborohydride as the reducing agent.




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[*] posted on 7-10-2022 at 09:23


Hi Lionel.
cyanoborohydride are far from possible for me. And yes it's true it can over methylate, but generally Tertiary amines are done there way with reasonable yields.
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[*] posted on 13-10-2022 at 12:02


A few links of interest:

http://www.chm.bris.ac.uk/motm/nicotine/E-synthese.html#:~:text=(S)%2Dnicotine%20is%20the,a%20racemic%20preparation%20by%20recristallisation.

https://pubs.acs.org/doi/10.1021/acs.orglett.8b03909

https://tobaccocontrol.bmj.com/content/early/2021/09/07/toba...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811585/

https://patents.google.com/patent/CN110256403B/en
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[*] posted on 13-10-2022 at 13:54


Kinda wonder if you could do it with a 1,3-dipolar cycloaddition of methyl acrylate or a similar C2-synthon onto the azomethine ylide formed by decarboxylative addition of sarcosine to nicotinaldehyde followed by decarboxylation



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[*] posted on 13-10-2022 at 15:40


It is hard to make it cheap enough, compared to extracting it from tobacco not good enough to use in cigarettes. Me being in NC, it used to be available very cheap, but there is less grown now in the US, but more in other countries, where it is much cheaper. Also, the source does not matter now, as the FDA regulates all nicotine products now due to changes in the law. It is not very expensive, but the sale is now more regulated than before due to so many people trying to make vaping products, and many not knowing what they are doing.

I have seen bottles of it in the past, used more as a pesticide than for synthesis. A tiny amount will kill virtually any bug in seconds, and people too. People complain about neonicotines, but they are way safer to mammals than nicotine, but very toxic to bugs, including bees and butterflies. Good on termites also.
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