Author Topic: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction  (Read 732 times)

Evilblaze

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P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« on: May 09, 2010, 11:26:55 PM »
The idea....

There is a synth /1/ on Rhodium for P2P from benzyl-magnesium-chloride and acetonitrile. And there is another synth /2/ from the same imine (what is produced from the benzyl-magnesium-chloride and the acetonirile) is to hydrogenated to amph.

On SM /3/ there was someone who tried it out, but he used THF instead on ether and it ruined the whole reaction. He got bad yields with the P2P and there was no other report except what is on Rhodium. Here the yields what were reported by Poodle /1/ seems more than good (+75%).

The reaction would go on this way:
React the benzyl-magnesium-halide with the acetonitrile in ether to obtain the imine as it is described in /1/. This product would be filtered out from the reaction mixture. It would be dissolved in MeOH and it would be hydrogenated by aluminum and methanol to amph.

Instead of the platinum aluminum and methanol was used. Easier and cheaper...


Experimental part....

The grignard reaction between the (25g) benzyl-chloride and magnesium started slow. The magnesium was activated with iodine in methanol. When the fizzing started and the MeOH started to boil, the magnesium was filtered and added to the ether/benzyl chloride mix. The grignard reaction stared slow, but after 2 hours it just boiled. The temperature was kept under 40 Celsius. Because of the time, just the half of the grignard reagent was prepared... So some benzyl chloride was left in the mix.

The reaction between the acetonitrile and the benzyl chloride was the best part. When the acetonitrile was added a white participate formed. This was filtered (somehow a part of this slurry went through the filter).

There was 3 solution.
Solution one was the liquid what was left after from the acetonitrile and benzyl chloride reaction. Almost no white participate was in it, but a lot ether was in the solution. It was quite dilute.
Solution two was the liquid what was filtered. The white/gray participate. This was dissolved in methanol.
Solution three was the liquid what was left after the filtration, much white participate in it.

Sol. 1 was reacted with MeOH + Al. This was used to hydrogenate it, instead of the sodium borohydride.
After the reaction occurred, the solution was poured on ice cold water (a lot Al(OH)3 formed), this was reacted with cc HCl and than NaOH was added to pH 14. A the honey was collected and the sulfate salt was made from it.

Sol. 2 was reacted with MeOH + Al. The reaction was going on 50 Celsius. And the yield was 0. It was poured it on ice, added HCl and NaOH until pH 14 but no honey.
Conclusion: just dilute solutions of this thing should be hydrogenated and not the concentrated solution.

Sol. 3 was poured on water and cc. HCl was added. P2P formed in 80% yield, awesome ;D


References
/1/: https://www.erowid.org/archive/rhodium/chemistry/phenylacetone.html#grignard
/2/: https://www.erowid.org/archive/rhodium/chemistry/amphetamine.html
/3/: http://www.sciencemadness.org/talk/viewthread.php?tid=5519#pid64089

Pictures and everything else data is coming soon, this was just a "test".

shroomedalice

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #1 on: May 14, 2010, 11:36:29 PM »
I think you will find due to the product being an imine that a simple Al/Hg reduciton will work for making amphetamine.
is this what you mean by aluminium and methanol.

other than that very nice work.

I have often thought of doing this reversed ie with PAN and methyl magnesium bromide.

Evilblaze

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #2 on: May 15, 2010, 11:32:59 AM »
I think you will find due to the product being an imine that a simple Al/Hg reduciton will work for making amphetamine.
is this what you mean by aluminium and methanol.

I've just thought many types of reduction, instead of the Al/Hg, but there was a BIG problem.

The imine what is made from this reaction is sensitive to two things: water and acids. So the original Al/Hg reduction is not a good idea, because a lot GAA goes in it what is not good for the imine, it will hydrolyze to P2P in a minute.

I've needed a reduction what is simple and it is pH +7. The best would be to use borohydrides or aluminiumum hydrides, but these are really expensive (but I will make a small scale run with them just for the yield ;)). So, the next idea was the MeOH/Al reduction. Simple, easy and cheap, What else is needed?

The only big problem was, that the imine is sensitive to heat, so the reduction should go under 35 Celsius (this is what I discovered too late...). On the next run it will be cooled with a water bath and we'll see the yields.

If anyone has any other idea for the reduction, I would be happy if he would post it, thanks!

shroomedalice

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #3 on: May 18, 2010, 05:15:57 AM »
why would you put acetic acid in the amalgum.

I would just use IPA mercury salt and Al foil.

it looks to be just an imine not a nitrostyrene to me so no need for acidic enviroments.


Evilblaze

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #4 on: May 23, 2010, 10:57:31 PM »
Another run. Another question.

Things are just aint going all right. So:

250g benzl-chloride 99% pure
60g magnesium shavings 99% pure
500ml diethyl ether 99,6% pure
130g acetonitile 99,8% pure
yield 88g P2P ?% pure

The grignard reaction was not ok. There was problems, like it didn't react. The white participate formed and the reaction slowed down. It was left to stand for 2 days, sometime it was stirred, but the magnetic stirrer didn't had enough power to mix the slurry.



Circa half of the magnesium reacted.
The reaction mixture was decanted and filtered to get rid of the unreacted magnesium, and the acetonitrile was added as a 75% solution in ether. A white participate formed immediately, it was hard to stir the solution.

This mix was decanted again and white stuff what was left, was added to slowly to 1000ml of water with stirring. After the addition, 200ml of 35% HCl was added to hydrolyze the imine to P2P. A yellowish oily layer formed on the top of the water. Most of ether, but there was also P2P in it.
The oily layer was washed with 30% HCl to make the HCl salt of the phenyl-2-benzylimino-propane whet dissolves in water and it won't be in the P2P.
Another wash was with boiling NaOH to get rid of the benzyl chloride and the ether was distilled off, yielding 100ml of P2P.




So.
How can the grignard reaction made in +80% yield, based amount on the reacted magnesium? Because I have no idea.
How can the phenyl-2-benzylimino-propane separated from the P2P in 100%? Because there were huge crystals in the P2P after cooling it down (3%).
« Last Edit: May 23, 2010, 11:02:10 PM by Evilblaze »

lugh

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #5 on: May 24, 2010, 12:45:56 AM »
You have an organic product layer that you are calling p2p  :P  Chemists generally do some sort of qualitative testing to determine the identity of the product of their experiments, in the old days this was done via derivatives which had known melting points and nowadays it's usually done with various instrumental means of chemical analysis  ;) One derivative of phenylacetone that's well known to the swarm is the bisulfite adduct, that's not definitive but it does narrow down the field of suspects to aldehydes and methyl ketones   :-\  You can't just assume this reaction works the way that you think it will, you have to have data to support your hypothesis  8)
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Evilblaze

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #6 on: May 24, 2010, 01:05:06 AM »
You have an organic product layer that you are calling p2p  :P  Chemists generally do some sort of qualitative testing to determine the identity of the product of their experiments, in the old days this was done via derivatives which had known melting points and nowadays it's usually done with various instrumental means of chemical analysis  ;)

We've checked the melting point, the density and we've made reactions with this oil and at the end of the other reactions the other compounds physical properties were ok.
And maybe I can check it with NMR... But it will be in the future.

lugh

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #7 on: May 24, 2010, 12:11:27 PM »
Two other derivatives that are useful in determining whether one has phenylacetone are the semicarbazone and the oxime  ;) The melting point of the semicarbazone is known, and the oxime can be easily reduced to amphetamine which can be evaluated for biological activity  ;D The use of derivatives is an almost lost art in chemical analysis, but these methods are what's most useful to a member of the swarm  8)
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Wizard X

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #8 on: May 25, 2010, 12:40:56 AM »
Determination of 2,4-Dinitrophenylhydrazones and Semicarbazones by N.m.r. http://pubs.acs.org/doi/abs/10.1021/ja00864a015

phenylacetone semicarbazone, m.p. 186-187 oC.


The spectrophotometric determination of phenylacetone in amphetamine. http://www3.interscience.wiley.com/journal/113357734/abstract?CRETRY=1&SRETRY=0
Stanley K. Freeman
Benzol Products Company, Newark, New Jersey

Abstract
A rapid and precise method is described for the ultraviolet spectrophotometric determination of phenylacetone in amphetamine. The absorbances of ethanolic solutions of the amine containing up to 10 per cent of ketone are measured at 290 m and the amount of phenylacetone present read from a standard curve. There is good correlation between purity of amphetamine samples examined and their phenylacetone content.
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Enkidu

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #9 on: May 25, 2010, 07:50:03 PM »
How can the grignard reaction made in +80% yield, based amount on the reacted magnesium? Because I have no idea.
How can the phenyl-2-benzylimino-propane separated from the P2P in 100%? Because there were huge crystals in the P2P after cooling it down (3%).

Thanks for posting a writeup.

In order to get your grignard kickin, you must have COMPLETELY anhydrous rxn conditions. Flame dried glassware, sodium dried solvents, etc. Of course, you don't have to use sodium, but you've got to get that ether anhydrous.

As for the alkylation of the ketimine salt, does that happen? If it does, just hydrolyze with dilute HCl (which in turn reacts with the benzylamine and forms the salt) and then extract the organic layer.

Sedit

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #10 on: May 25, 2010, 08:41:35 PM »
Flame drying can be accomplished in a Microwave pretty well. MW the flask for about 1-2 minutes and you will see the flask sweat at this point with water vapor inside of it even if you thought it was dry. Allow this to set for a second because it holds heat and the vapors will mostly leave over this time. Then MW it again for about 2 minutes. As soon as it cool enough to handle cover the top in Al foil and tape.

This is the process I used for all my Li[NH3]4 experiments and it worked really well. Over at Sciencemadness there is a very recent thread where the fellow dryed is Ether with nothing more the CaCl2 IIRC and his grignard took off without a hitch so I think even though it is prudent to dry everything as much as you can its not as dier as people make it seem. As soon as I get some good Mg im going to perform a Grignard in a beer bottle for spite using EtBr + Mg because someone challenged me and im not one to turn down a good challenge. I have been considering drying mine with Activated Al since I feel that should work very well in dryng it the way I need. Either that or Li which should work as well without the possibility of messing around with Hg.

How about feeding a small amount of dry HCl into Et2O dryed with MgSO4 and after adding the HCl place some Aluminum foil to help scavenger the H2O and HCl left around. Follow with a distill should work I think.

Granted im talking here with no first hand experiance but I think people stress themselfs abit over the grignards dryness since Mg itself will in time act like a drying agent. Just a matter of the unpredictability IMO since you don't know hw long it will take before it reaches the state needed to get rolling.
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micro

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #11 on: May 29, 2010, 10:33:03 PM »
This is the process I used for all my Li[NH3]4 experiments and it worked really well. Over at Sciencemadness there is a very recent thread where the fellow dryed is Ether with nothing more the CaCl2 IIRC and his grignard took off without a hitch so I think even though it is prudent to dry everything as much as you can its not as dier as people make it seem. As soon as I get some good Mg im going to perform a Grignard in a beer bottle for spite using EtBr + Mg because someone challenged me and im not one to turn down a good challenge.

Yeah! We want you to be truly dangerous!
But on the subject of beer bottle Girnard, I compleatly beleive that it is possible, it just putts some challenges on drying the "glassware".

Evilblaze

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #12 on: May 29, 2010, 11:55:53 PM »
Third run, I think I'm going mad >:(

The reactants:
100g benzyl chloride
60g magnesium
300ml diethyl ether
can't remember the amount of the acetonitrile 60 or 70g.

The yield of the P2P... 30ml. Sucks.

The problem was the gignard reagent what was made in the reaction didn't dissolved in the ether and it was like a layer what prevented the magnesium to react with the benzyl chloride. The mix was stirred with a magnetic stirrer, but the whole reaction turned into a slurry mass and the magnesium didn't dissolved. Only 20g from it.
All of the reagents were pure, not homemade. The only water was in the ether: 0,001%, but this is almost nothing. The glasses was also dried properly. 
The magnesium was activated in boiling IPA with some iodine.

So. How can I make a good yielding grignard? More ether? It cost's much and for 100g benzyl chloride 600-800ml ether would be really much. But if no other ideas, than I have to do that.
Maybe add some other solvents. Like toluene?

I've need a solvent what doesn't form an azeotrope with the ether, so the temperature of the reaction won't go up too much. And it should be cheap.

Naf1

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #13 on: May 30, 2010, 12:55:01 AM »
Not only do your reagents have to be super anhydrous, but also excess oxygen and carbon dioxide from the atmosphere will ruin this reaction(the reaction with carbon dioxide will produce phenylacetic acid). And after fitting a drying tube, the apparatus is generally purged with inert gas before starting (Helium, Hydrogen, Nitrogen). Helium is available at party supply places, small nitrogen cannisters available for paint ball guns (and they can also refill it for you also) and hydrogen although dangerous can be generated (enough to fill a balloon which you can purge with). I would be following the orgsyn style procedure rather than the one from rhodiums archive!

Quote
n-PROPYLBENZENE
Organic Syntheses, Coll. Vol. 1, p.471 (1941); Vol. 4, p.59 (1925).
Submitted by Henry Gilman and W. E. Catlin.
Checked by C. S. Marvel and H. R. Snyder.

In a dry 3-l. flask, fitted with a mercury-sealed stirrer, a 500-cc. dropping funnel, and a condenser provided at its upper end with a drying tube containing a mixture of calcium chloride and soda-lime (Note 1), is placed 48.6 g. (2 atoms) of magnesium turnings. There are then added 200 cc. of dry ether, a small crystal of iodine, and about 25 cc. of a solution of 253 g. (230 cc., 2 moles) of freshly distilled benzyl chloride in 1 l. of dry ether. If the reaction does not start at once, the flask is partially immersed in a bath containing water heated to about 40°. As soon as the ether begins to boil, and reaction sets in, the bath is removed and stirring is commenced. The remainder of the benzyl chloride in ether can be added during the course of one-half hour if the reaction is regulated by cooling the greater part of the flask by immersion in ice water (Note 2). The reaction will continue for about fifteen minutes after all the benzyl chloride has been added, and then the mixture is refluxed gently for about fifteen minutes.

  • 1. The function of the calcium chloride and soda-lime is to absorb any moisture and carbon dioxide which might diffuse into the reaction flask. The deleterious effect of another constituent of the atmosphere, oxygen, may be decreased by first sweeping out the flask with dry nitrogen or hydrogen. The initial use of a dry inert atmosphere may also be supplemented by the use of a trap1 to exclude the air, particularly in those operations requiring extensive periods.
  • 2. Benzylmagnesium chloride is one of a group of Grignard reagents which can be prepared in satisfactory yields by the rapid addition of the halide to magnesium in ether.2
  • 3. If the diethyl sulfate is dark in color it should be washed, prior to distillation, with ice water and then with a sodium bicarbonate solution until all free acid is removed.
  • 4. At the end of this time a negative color test shows that the Grignard reagent has been used up.
  • 5. The solution is refluxed with alcoholic alkali to decompose any unaltered diethyl sulfate.
Gilman, Zoellner and Dickey, J. Am. Chem. Soc. 51, 1583 (1929)

http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv1p0471#Ref472N2

If you wanted to test the grignard reagent you could take a sample and bubble in CO2 which would produce nearly quantitative yields of easy identified phenylacetic acid.

edit; Obviously one would scale back the ether, and use that grignard as quickly as possible!
« Last Edit: May 30, 2010, 01:19:40 AM by Naf1 »

Naf1

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #14 on: May 30, 2010, 03:37:26 AM »
Searching through OrgSyn, there is also another procedure that uses more appropriate amounts of ether. And seems using a similar method as above; dry as possible, make an ether/magnesium solution and add the benzyl chloride. The method below adds the halide as quickly as you possibly can without having ether fumes escaping your condenser, or running away, and is controlled also by cold water (towel). They omit the use of a drying tube and a purge in the below procedure, maybe because of the inevitable positive pressure that will be created from boiling ether? I have not tried that procedure, but would not be suprised if they just expected you to know that it should be done ??? But it may also work? Previously I have used drying tube with calcium chloride but no soda lime and an inert purge, using a method nearly identical to the one above as the halide in question took a fair amount of ether to dissolve it, with a slower dropwise addition of the ether/halide to ether/magnesium with good results. But this procedure may work just as well?

Quote
In a 3-l. three-necked flask, fitted with a mechanical stirrer, a reflux condenser, and a separatory funnel, are placed 24.3 g. (1 gram atom) of magnesium turnings, 500 cc. of absolute ether, a crystal of iodine, and a 5- to 10-cc. portion of 126.5 g. (115 cc., 1 mole) of freshly distilled benzyl chloride (b.p. 177–179°). In a few minutes the reaction starts (Note 1) and is controlled if necessary by cooling with a wet towel. The stirrer is started, and the balance of the benzyl chloride is run in as fast as the refluxing will permit. The addition requires from one to two hours, and when completed the mixture is refluxed on the steam bath with stirring for three hours. With the stirrer still running, 182 g. (1 mole) of benzophenone (Org. Syn. Coll. Vol. I, 1941, 95) dissolved in 500 cc. of absolute ether is added at such a rate that the mixture refluxes rapidly. This requires about twenty minutes, and then the reaction mixture is allowed to stand for two hours (Note 2).

1. If the reaction does not start within thirty minutes, the mixture is warmed on a water bath with the stirrer running.
2. Slightly better yields are obtained if the reaction mixture is allowed to stand overnight.
http://www.orgsynth.com/orgsyn/prep.asp?prep=CV2P0606

Enkidu

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #15 on: May 30, 2010, 06:12:28 AM »
More ether? It cost's much and for 100g benzyl chloride 600-800ml ether would be really much. But if no other ideas, than I have to do that.

Why not run micros? Use only a gram or two of each reactant. You should always do that until you have perfected the rxn...

sloppy

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #16 on: June 30, 2010, 03:15:06 AM »
I have an odd question....I've looked in my handbook of chemistry for a definition in the index, and elsewhere, but couldn't find any info. UTFSE didnt accomplish anything either, so here goes....

"In a dry 3-l. flask, fitted with a mercury-sealed stirrer, a 500-cc. dropping funnel, and a condenser provided at its upper end with a drying tube containing a mixture of calcium chloride and soda-lime (Note 1), is placed 48.6 g. (2 atoms) of magnesium turnings."

The question is, what does the (2 atoms) mean or signify??

nk40ouvm

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #17 on: June 30, 2010, 04:56:23 AM »
I have an odd question....I've looked in my handbook of chemistry for a definition in the index, and elsewhere, but couldn't find any info. UTFSE didnt accomplish anything either, so here goes....

"In a dry 3-l. flask, fitted with a mercury-sealed stirrer, a 500-cc. dropping funnel, and a condenser provided at its upper end with a drying tube containing a mixture of calcium chloride and soda-lime (Note 1), is placed 48.6 g. (2 atoms) of magnesium turnings."

The question is, what does the (2 atoms) mean or signify??

"Atoms" here = "gram atoms" = moles.

2 moles of Mg (atomic wt 24.3) = 48.6 grams.

sloppy

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #18 on: July 01, 2010, 12:15:41 AM »
ahhh. If it said "mole" id have known, but the 2 atoms makes sense now. Thanks nk

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Re: P2P or amph. from benzyl magnesium chloride and acetonitrile grignard reaction
« Reply #19 on: July 02, 2010, 03:19:13 AM »
I have often thought of doing this reversed ie with PAN and methyl magnesium bromide.

Actually this reaction does not yield p2p-imine as a product.
See: http://forums.blacklight.me/viewtopic.php?f=22&t=1101