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Author: Subject: troubleshooting microwave synthesis of melatonin.
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[*] posted on 22-1-2014 at 03:36
troubleshooting microwave synthesis of melatonin.


hey all. quick disclaimer, i guess technically this is not amateur chemistry, as i'm doing this as part of my uni labs, but i figured it may be of interest to some people here and maybe some of you will be able to help me out.

I'm trying to do a synthesis of 5 methoxy tryptamine en route to melatonin, in previous years a microwave route was used (http://bitnest.ca/Rhodium/pdf/melatonin.microwave.pdf) but at some point the special microwave reactor stopped working. I'm trying to do the route without a microwave but the reaction times are much longer. There are a bunch of domestic microwaves (set up with air condensers that are used for some inorganic labs) that i have access to. Trying scaled down versions of the first two steps led to a mixture of products (step 2-3 gives 6 spots on tlc from rxn mixture pre workup) with quite some charring. I feel there is potential as the non microwave proceedure took many many hourse without seeming to reach completion (by tlc).

I was wondering if anyone had any practical experience working with domestic microwaves in organic synthesis or if anyone had suggestions of things i might try...?

the paper is a little vague on the details of their microwave set up, as far as i can see. they state that they use a MCL-T domestic oven with a maximum output of 850W but don't say what power they have the microwave set on, or how high a temperature they let the substrate get to, or whether they do the reaction in a sealed or open vessel.

maybe the reaction should be done in a closed vessel and the evaporation of the solvent (into the condenser) results in the charring?

perhaps scaling down (10:1) results in more charring somehow, maybe i should try scaling back up?

maybe the charring is a result of too high a microwave power and i should try it at a lower wattage?

any thoughts are much appreciated! x

<!-- bfesser_edit_tag -->[<a href="u2u.php?action=send&username=bfesser">bfesser</a>: corrected subject typo "mleatonin"]

[Edited on 23.1.14 by bfesser]
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[*] posted on 22-1-2014 at 06:47


Quote: Originally posted by melatonin  
I'm trying to do a synthesis of 5 methoxy tryptamine en route to melatonin, in previous years a microwave route was used (http://bitnest.ca/Rhodium/pdf/melatonin.microwave.pdf) but at some point the special microwave reactor stopped working.

So, you are saying that you actually used the procedure from that Synthetic communications article and it worked? I find it hard to believe you. That article has many suspicious claims and I would personally not trust it at all.
Quote:
I was wondering if anyone had any practical experience working with domestic microwaves in organic synthesis or if anyone had suggestions of things i might try...?

There is no reason to apply a domestic microwave oven for a reflux reaction where the reaction mixture is homogeneous (like the 2->3 transformation is). It barely has any influence in comparison to conventional heating, if any at all.
Quote:
the paper is a little vague on the details of their microwave set up, as far as i can see. they state that they use a MCL-T domestic oven with a maximum output of 850W but don't say what power they have the microwave set on, or how high a temperature they let the substrate get to, or whether they do the reaction in a sealed or open vessel.

You cannot measure the reaction temperature in a domestic oven. Uttmost, you can check the reaction mixture temperature after you finished the heating. You need a microwave reactor for temperature controlled heating, which is something very different (a MW reactor is a MW-heated autoclave). You also don't put a sealed vessel in the domestic microwave oven, if you value your life. In general, you don't do such stupid things with domestic microwave ovens.
For a reflux set up, a hole is made at the top of the oven for the condenser. See the relevant thread about how this is done without self-injury.




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[*] posted on 22-1-2014 at 07:09


I have to agree with Nicodem on that. We have used microwave reactors, and while there are some cases where they are useful, it is mostly for smaller sealed tube reactions where they simply allow us to heat them quickly, and with careful control of the temperature and pressure. In most cases when we wanted to scale up the reactions, we either went to normal chemistry with lower temps and longer times, or we went to high pressure reactors, where we often saw similar results to the microwave systems.

If you have access to thick walled glass pressure tubes, they can be used in some cases, behind shields, to test the same types of chemistry, if you heat them with an oil bath or other gentle means. Ace makes some great ones, up to several hundred ml. Bigger than that, I would go to a steel reactor with temperature and pressure controls. None of that chemistry is anything special, other than the yields claimed. If there is no special catalyst or other process then thermal heating will accomplish the same result as microwaves. There are cases where metals or special solvents can generate very high localized temps in a microwave, but I don't see anything in this route that appears to be that case.
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[*] posted on 22-1-2014 at 08:15


The remarkable similarity of that route to the classical Japp-Klingemann reaction and the non-sense chemistry made me check the literature.
It appears the Synthetic communications article is a wannabe plagiarism of a 3 years older article published in a Chinese journal (Disi Junyi Daxue Xuebao, 2000, 21, 949-951) where a synthesis of melatonin is described, employing the Japp-Klingemann reaction:
Quote:

Chem. Abstr. 134: 222590

Synthesis of melatonin-​a new sleeping drug
By: He, Wei; Li, Xiaoye; Zhang, Bangle; Li, Zhongjie

Melatonin was synthesized by substituting 1,​3-​dibromopropane with phthalimide in the presence of K2CO3 by refluxing for 7 h to obtain N-​(3-​bromopropyl)​phthalimide, substituting with Et acetylacetate in the presence of K2CO3 by refluxing for 3 h, extg. with Et ether to obtain Et 2-​acetyl-​5-​(2-​phthalimidoethyl)​pentanoate, allowing to react with 4-​methoxybenzenediazonium chloride at o° for 1 h and at pH 5-​6 for 3 h to obtain 2-​ethoxycarboxyl-​3-​(2-​phthalimidoethyl)​-​5-​methoxyindole, hydrolyzing with 2M NaOH in the presence of catalyst by refluxing for 2 h and with H2SO4 by refluxing for 5 h, extg. with dichloromethane to obtain 3-​(2-​aminoethyl)​-​5-​methoxyindole, and acylating with acetic anhydride at 0° for 1 h. The total yield was 37.1​%.

It appears the "new authors" did not even understood what a Japp-Klingemann reaction is, and while writing the new article, wrote a reaction of phenylhydrazine with a 2-alkylacetoacetate ester to give an 2-indolecarboxylate ester instead of the Japp-Klingemann as in the original article. This would be a new reaction, yet the "authors" don't even mention the importance of this "discovery". This apparent ignorance of such a discovery made me check the literature for any such transformations and not surprisingly this article gives the only relevant hit by a SciFinder search!

Otherwise, the Japp-Klingemann reaction was used for the synthesis of tryptamines by several authors: Archiv der Pharmazie, 1978,311, 954-960, US20050245585 (published also in Synthetic communications, 43, 3294-3306), Tetrahedron, 2004, 60, 8829-8837, ...




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[*] posted on 23-1-2014 at 01:46


thanks so much for the speedy responses!

I haven't run the reaction successfully no.

the synthesis of methoxy tryptamine is a synthesis route that has been part of the course i'm on for some years (so i'm told) and the synthetic communications paper was one of the lead references given. I was told that in the past the reactions were done in specialized microwave reactor ( i dont know how well/ if the reactions used to work) with temperature control in a sealed vessel, but i couldn't find reference to any of this in the paper and as such was not sure how, if at all it could be adapted to 'work' in a domestic oven. I guess i was too trusting of the paper, and perhaps learning to culture a level of mistrust towards publications is part of the objectives of this lab course :P


Quote:

There is no reason to apply a domestic microwave oven for a reflux reaction where the reaction mixture is homogeneous (like the 2->3 transformation is). It barely has any influence in comparison to conventional heating, if any at all.


i did do a small scale test reaction of the condensation reaction between the n bromopropyl phtahlamide and acetoacetate in the microwave. After around 5 minutes the TLC was showing spots essentially equivalent to those taken from the non microwave mixture after having been refluxing for many hours. I did not isolate the product (and then proceeded to carbonise it due to a lapse of concentration) so i cant infer much, but shorter reaction times are a possibility with even open vessel microwave reactions are they not?

either way, thanks for the advice, i guess i'll stop trying to progress down that path and focus on a non-microwave synthetic route.
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[*] posted on 23-1-2014 at 06:36


There may be cases where localized super-heating may allow reactions to proceed faster in the microwave. But what I have seen is that many microwave reactions that are open to the environment simple evaporate much of the solvent, thus raising the temperature of the reaction by removing the lower boiling solvents. For sealed pressure tubes, you are simply raising the BP by raising the pressure, just like a pressure cooker used to can veggies.

In many cases the reactions can be sped up by simply changing the reaction conditions, going to a higher boiling solvent system (I have even resorted to using Dowtherm A at 200-300 C), finding better reagents, changing acids/bases, etc. That is why chemistry is an empirical science, as there are many ways to improve reactions, and there is no simple magic (microwave) bullet for all chemistry. But sometimes the improvements reported for some reactions are also exaggerated (that is the polite term), so don't expect every literature report to be repeatable.

In the case of the small scale experiment that was moving forward at 5 minutes, if the reaction was refluxing, it would not have carbonized due to a lapse in concentration, as the temperature could not have gone above the BP, so what you may have done is to evaporate the solvent , concentrating the reaction (which will often speed it up) and/or created a melt. It may be that doing the reaction as a melt, in a higher BP solvent, or at a higher concentration will accomplish the same goal without the microwave, and in a more controllable manner.
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[*] posted on 26-1-2014 at 13:20


Quote: Originally posted by Nicodem  

....
You cannot measure the reaction temperature in a domestic oven. Uttmost, you can check the reaction mixture temperature after you finished the heating. You need a microwave reactor for temperature controlled heating, which is something very different (a MW reactor is a MW-heated autoclave). You also don't put a sealed vessel in the domestic microwave oven, if you value your life. In general, you don't do such stupid things with domestic microwave ovens.
For a reflux set up, a hole is made at the top of the oven for the condenser. See the relevant thread about how this is done without self-injury.


SorryNicodem, as much as I dislike to contradict my favorite moderator, but you can measure temperature in a household microwave pretty well, actually an old MIELE I owned had a thermocouple and a plug insides the cavity for exactly this purpose.
No big surprise this model was also sold by MERCK as microwave reactor - slightly modified except for the price which was heavily modified.

If one is about to heat a sealed vessel there are only few places imaginable which are safer to do this then the cavity of an old heavy microwave. Old quality micros resemble pretty much a tank or a safe, double steel walls, what do you want more?

Attached is the article describing how the temperatur measurement can be done , another article I cannot find now accomplished tis by using shielded and grounded thermocouples. They have to be re-calibrated and thats that IIRC.

Attachment: Thermocouples in MW howto.pdf (1.4MB)
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