Author Topic: Novel high-yielding C=C reduction of nitrostyrenes  (Read 34917 times)

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Tricky

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and
« Reply #40 on: October 03, 2003, 03:47:00 PM »
SWIT also has tryed reduction with PTC - result was the same - tar  :(  :(  :(

PS, 2,5DMNS which used for rxns was produced by EDDA method without recrystallisation - may bee it's my problem???


starlight

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difficult
« Reply #41 on: October 03, 2003, 04:22:00 PM »
this seems like a tricky reaction. I have achieved red goo from the IPA/H2O reduction of 2,5DMNS when using the above text. Not sure why. My 2,5DMNS crystals were pretty big and did not dissolve at first so I had to crush them fine to get the reaction going. Also had to raise the temp to around 35C before the reaction would start. I added over course of 1hr in small portions (and added v. small amount of NaOH stabiliser to aqueous borohydride soln.)

Tricky

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another one...
« Reply #42 on: October 03, 2003, 06:11:00 PM »
To suspension of 75ml of toluene, 20,9g of 2,5DMNS and 1ml of Aliqute 336 was added solution of 4,2g NaBH 4 in 15ml of water (containing 50mg of NaOH). Mixture was violently stirred. The nitrostyrene dissolved after apr. 5-10 minutes. Temperature rose and foaming had placed. On the bottom of beaker the white goo was formed. After 1 hour temperature decreased till room and no rxn was observed (f.e. gas isolation). Mixture was: the toluene (yellow-orange) layer and white goo on the bottom. Then the 50% GAA was added till the sticky layer became the water (pH = 4). After separating and solvent evaporatig SWIT has a very dark red oil, which is not tar.
So, I have some question about process of above.
1. Is the final product consist of true nitroethane or it's a shit?
2. How one can purify it? Vacuum distilling or someone else?
3. Is it enough of water aspirator for distill this product?
4. And how long 2,5-DM-Phenyl-2-Nitroethan may storage.

Thanx for advice.
And sorry for my bad english.


Barium

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Fuck!!
« Reply #43 on: October 03, 2003, 06:37:00 PM »
Am I going dyslectic or what?  :-[  I need to have someone else read and correct errors before I post methods nowdays.

I see now that I wrote 50 ml water and 25 ml IPA in the protocol. It should be the opposite, 50 ml IPA and 25 ml water. One can actually use even less water, 15 ml is enough. This red tar haunts me too now and then. And I hate it. The tar appears when the post-reaction mixture is acidified, particulary with strong acids like hydrochloric acid or sulfuric acid. But it appears even with acetic acid sometimes. I have found that there is no need to acidify at all. When the excess sodium borohydride is destroyed stop adding acid and saturate with sodium chloride. Collect the IPA layer and carry on immediately with CTH or Zn/HCOOH.


Tricky

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Thanx for corrections and specifications,...
« Reply #44 on: October 03, 2003, 07:24:00 PM »
Thanx for corrections and  specifications, Barium.

So, what about the procedure with PTC? What's a tricks can it consist?

I tryed 75ml of toluen instead of your 25 - is this big difference?

And what is the white sticky goo on the bottom after 20-30  minutes of rxn?

And the question of product storage and purification is urgent for me too.

Thanx one more    :)  for advice.


Rhodium

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I'll edit the original, if you point it out
« Reply #45 on: October 03, 2003, 11:45:00 PM »
Barium: Exactly which post is it that should be edited with the correct information?

Manichi

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Tricky: i tried it...
« Reply #46 on: October 04, 2003, 07:04:00 AM »
...quite some time.

I failed exactly like you said, got that damn sticky oil dar yellow then orange and then yield dropped heavily. I got those in IPA/water and in tolu/water/aliquat too.

IPA/water failed maybe because of Ba's little mistake, i will retry it this way without acidifying, like he said.

Tolu/aliquat failed pretty much. Then i decided to replace tolu by DCM and suddendly all went ok, i didn't have such an exothermic reaction, but a nice gentle one, it gradually become light yellow. Try it in DCM in place of tolu, still with aliquat and same solvents ratio. It work great. I guess the hardware store tolu contain impurities (MeOH?) that were responsible of the total fuckups i got from this one.

Also, when using EDDA to make the DMNS, it is always better to recrystallise it in Ethyl acetate after. You dont loss much at all and the purity is well increased. It help greatly in the next steps.

Also, as Ba assured me and now i know it is true, the nitroethane well done is stable. If the color change through the night, that mean you failed the reaction. Doing it in DCM the color stayed pale yellow for a day, then i used it. Otherwise i had the color changing after a few minute to a few hours, and it ppt outta the toluene solution i did with it for washes, the sticky orange oil fell out.


1. Is the final product consist of true nitroethane or it's a shit?
2. How one can purify it? Vacuum distilling or someone else?
3. Is it enough of water aspirator for distill this product?
4. And how long 2,5-DM-Phenyl-2-Nitroethan may storage.


1. Both, if it change color to orange it´s shit. If it is stable pale yellow it´s nitroethane.
2. No need to purify except maybe washes.
3. No, dont need to distill it anyway.
4. More than one day if properly done, less than half a day otherwise.


Barium

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White goo
« Reply #47 on: October 04, 2003, 11:48:00 AM »
The reduction with Aliquat 336 or some other PTC works very well, but the PTC is impossible to separate from the nitroalkane unless one distills the mixture. Some CTH reductions of nitroalkanes to aminoalkanes works fine with the PTC hanging around. Other CTH reductions are disturbed and the catalyst poisoned. I have yet no clue why this is. But I'm working on it.

I tryed 75ml of toluen instead of your 25 - is this big difference?

Not at all. Toluene is completly inert to the reaction. But make sure the toluene does not contain impurities which reacts with the borohydride.

And what is the white sticky goo on the bottom after 20-30  minutes of rxn?

Borates from the oxidation of the borohydride.


The pure nitroethane is very stable and can be stored for at least a year in the fridge. Any change in color - from clear yellow to red - indicates decomposition. The products from the decomposition makes it impossible to get good yields, at least from a CTH reduction.  I haven't tried to reduce a partially decomposed nitroethane with Zn/HCOOH yet so I don't know if that reduction system still gives good yields.

It seems to be very important to have a good quality of 2,5-dimethoxy-beta-nitrostyrene in this reduction to avoid the red tar. Other nitrostyrenes does not seem to be as sensitive.


dr_mabuse

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Zn/HCOOH on partial decomposed nitroethane failed
« Reply #48 on: October 04, 2003, 04:45:00 PM »

I haven't tried to reduce a partially decomposed nitroethane with Zn/HCOOH yet so I don't know if that reduction system still gives good yields.


I tried to reduce the red oil with Zn/HCOOH, after workup and gassing with HCl, only tar fell out of, that was impossible to clean with acetone.


Tricky

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It seems to be DCM is the right answer.
« Reply #49 on: October 04, 2003, 05:35:00 PM »
Hi.
Some hours ago SWIT has repeated the same old rxn with PTC and DCM as solvent.
After separation, oil was washed with water and then with 10% GAA.
Result (first) - turbid yeallow oil, not clear (mixture with DCM).
So, I think about vacuum distilling now. But I have only water aspirator. Please prompt me - is it normal or can I lose my product (may bee for this nitroethane one needs more higher vacuum pump)???
And special question for Barim: Is the Aliquat 336 can poison the catalyst in Pd/am.formate system or it will work normal?


Barium

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It should not be a problem to remove the last...
« Reply #50 on: October 05, 2003, 11:11:00 AM »
It should not be a problem to remove the last bit of DCM with a water aspirator. Just remove the DCM and carry on with the next reduction. Aliquat 336 seems to poison some types of Pd/C where othrers are unaffected. I think it is the PTC which poisons the catalyst but I'm far from sure yet. It could be something else. If you can, use KCOOH instead of NH4COOH as the hydrogen donor. The potassium salt is much more effective.


Bandil

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Barium> When you say: "Collect the IPA
« Reply #51 on: October 17, 2003, 01:17:00 PM »
Barium>

When you say: "Collect the IPA layer and carry on immediately with CTH or Zn/HCOOH."

Do you suggest that the nitropropane is isolated in the usual manner first, or is it possible to use the IPA/nitropropane in a Zn/HCOOH reduction right away? The usual formic acid reduction is usually conducted methanol, but i don't see a problem with doing in IPA instead. The worst "pollution" from the reduction should also be washed away with the water...

Regards
Bandil


Bandil

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Proof of concept!
« Reply #52 on: October 18, 2003, 09:34:00 PM »
One pot reduction of nitrostyrenes


Yeah baby, this method can be performed without working up the intermediate product. The method was tested with phenyl-2-nitropropene as substrate. This is very exciting!!

Borohydride reduction
2,4 g's of sodium borohydride was dissolved in 50 mL's of IPA and 20 mL's water. This was stirred for 3 minutes prior to adding the substrate.

8,15 g's(50 mmole) of phenyl-2-nitropropene(recrystallized once) was added to this in several small 1/4 g's portions over five minutes. A little bubbling was noticed and the yellow color dissapeard nicely within minutes. After the whole mess was added, the mixture was stirred for half an hour. The mixture was quenched with 50% acetic acid, untill fizzing ceased, and then an additional mL was added. The pH was 6 at the end. While stirring, the mixture was saturated with table salt and stirred for five minutes. Two layers formed, an upper yellow IPA layer and a lower water layer. The two layer's where separated, and the water layer discarded. a total of 45 mL's liquid remained.

Zinc reduction
The IPA layer was without additional fuzz(cleaning etc) put in a clean RBF and 9,1 g's non activated Zinc dust was added in one portion(the acid takes care of this in situ), and a reflux condensor attached. This was stirred violently, and 25 mL 85% formic acid was added over the course of 10 minutes. The reaction did not tend to boil over as much(no cooling needed), as when methanol is used as a solvent, quite nice  8) . The reaction temperature was about 70 degrees at it's max. After addition, it was stirred for an additional 15 mins.

Workup
The remaining Zinc and it's salts, where removed by filtration. 3/4 of the total volume where removed at atmospheric pressure and the residue taken up in 5% HCl which dissolved everything nicely. The mixture was very red at this point; reminded quite a lot about a post MDMA ketone reaction mixtures. This was washed three times with 20 mL's DCM which made the water phase almost colorless. This was basified and extracted with DCM and evaporated. About four grams of amphetamine freebase remained(marquis tested). This was dissolved in equal amounts of IPA, acidified with 96% sulfuric acid and 4 times volume of acetone was added. The whole thing was a slurry of crystals  :) . After filtration a LOT of amphetamine sulfate remained  8) . Yield where not measured, as this was a proof of concept run.

The total reduction time is 1½ hour from start to finish and everything seems to run very cleanly.

Quite a nice pseudo-one-pot amphetamine synthesis might i say  :P  This is a seriously good alternative for the lazy chemist that doesn't want to reflux all day long!

PS: The bioassay is VERY positive. Some dude, which i might now, ingested 35 mg's of the product prior to writing this text, and is now tingling all over *aaaaaahhhhh*


Chimimanie

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Thumbs up!
« Reply #53 on: October 18, 2003, 09:56:00 PM »
Very cool!  ;D

So nice!  8)

starlight

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well done bandil
« Reply #54 on: October 19, 2003, 10:20:00 AM »
well done - very interesting. cuts down on the work.

amphetamine sulfate is easier to crystallize than many amine hydrochlorides/sulfates that i have come across. It seems less sensitve to contamination by a bit of remaining nitropropene or other yellow/orange gunk. Others, for example DMMDA2 need to be much purer and I think that this one pot style may not work so well for them.

Barium

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Very nice
« Reply #55 on: October 19, 2003, 11:16:00 AM »
You are a very competent bee Bandil. Great work!  :)

GC_MS

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Confirmation
« Reply #56 on: October 20, 2003, 03:36:00 PM »
I have tried Bandil's procedure and found it to be working as advertized.

50 mmol phenyl-2-nitropropene with 1.5 eq sodium borohydride in a mixture of 50 mL IPA and 20 mL dH2O. Neutralizing the reaction mixture with 50% acetic acid (till gas evolution stops) is followed by filtering the mixture from insolubles. The insolubles are washed with 20 mL IPA and 5 mL dH2O. Table salt is added to the mixture and the yellowish IPA layer is isolated after filtration.

The IPA layer is added to a new RB, which is charged with some Zn. 25 mL HCOOH is added during 15 minutes. The mixture becomes warm but not hot. 45 minutes after final addition of HCOOH, Zn and its salts are filtered off. The volume of the filtrate is reduced to circa 20% and 10% aqueous HCl is added. The solution becomes cloudy and a red-like oily substance falls out. The aqueous solution is extracted with DCM, after which the aqueous layer is made alkaline with KOH. Amphetamine is extracted with DCM and precipitated with concentrated sulfuric acid.

The crystals are currently drying. As such, I can't give you the yields, but I don't consider it of primary importance.

GC-MS analysis of DCM-soluble impurities isolated after the Zn/HCOOH reduction indicated the presence of the following substances: phenyl-2-nitropropene, phenyl-2-nitropropane and phenyl-2-nitropropanone. There are many other impurities, but I have no clue about their identity. The three named substances stand for ca 90% of the total impurity amount. Of these three, phenyl-2-nitropropene was the most abundant impurity (followed by phenyl-2-propanone and phenyl-2-nitropropane).
GC-MS analysis of the amphetamine DCM extract indicated the presence of amphetamine (major compound) and - tentatively - phenyl-2-aminopropene (minor impurity). Also to be found in the reaction mixture: the analogue oxime (tentatively identified), amphetamine-benzaldehyde condensation product, amphetamine-P2P condensation product (rather abundant impurity as well...).

It should be noted that the impurity ratios can vary alot, depending on the purity of your substances. However, it gives an idea about what you can expect.


Bandil

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GC_MS> Yes that's great initiative you took
« Reply #57 on: October 20, 2003, 03:52:00 PM »
GC_MS>
Yes that's great initiative you took there. It's really cool to get some analysis of this method, as i don't have access to that!

Do you have any idea of how bad the pollution is compared to LAH reductions for example?

Regards
Bandil


GC_MS

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Reanalysis
« Reply #58 on: October 21, 2003, 02:35:00 PM »
OK, I did two different runs.

Run A

The same procedure as Bandil described. The Zn-salt filtrate was stored in the fridge (4°C) for two-three hours (there is no need to do this; I just had other things to do as well, but this "storing" might have had his effect on the reaction mixture content).

The acidified Zn-filtrate was reduced in volume and extracted with DCM; the organic layer was dried over Na2SO4 and a sample analyzed with GC/MS. The following substances have been retrieved (percentage stands for AREA% of TIC (40->500 amu)):

- phenyl-2-nitropropane (62.81%)
- phenyl-2-nitropropene (7.62%)
- phenyl-2-propanone (5.70%)
- N-formyl-amphetamine (4.69%)

The aqueous layer was made alkaline with KOH and allowed to cool down to RT. The turbid mixture was extracted with DCM (3 x 75 mL) and the combined organic layers dried over Na2SO4 to yield 2.7 g of a yellow oil. GC/MS analysis of this oil:

- amphetamine (40.66%)
- phenyl-2-propanoxime (28.87%)
- amphetamine-P2P imine (18.66%)
- amphetamine-benzaldehyde imine (1.04%)
- phenyl-2-propanol (1.02%)

Detected as well: N-[2-(1-phenylpropyl)]-ethylidenimine (cf Comments & Additional Information at the end of this post).

Run B

A second run was performed. The working concept is still the same, but conclusions I made based on the results from A enforced me to modify the procedure.

150 mmol phenyl-2-nitropropene (recrystallized twice after synthesis, high GC purity) was suspended in a mixture of 150 mL IPA and 50 mL dH2O. The suspension was stirred vehemently while 2 mol eq sodium borohydride was added over 20 minutes. The reaction was allowed to continue for another 45 minutes, after which GAA was added to neutralize residual NaBH4; the liquid phase was filtered off and the borate cake rinsed with a small amount of IPA/dH2O. The filtrate was treated with table salt and the IPA layer isolated.

The IPA layer was introduced in a three-necked 1-L RB equiped with stirbar and reflux condenser, which was charged with 10 mol eq untreated Zn powder (relative to the amount of phenyl-2-nitropropene). A total of 3 mol eq HCOOH (98%, relative to the amount of Zn) was added over 20 minutes.

The Zn-salts were filtered off and the filtrate reduced in volume. Its colour was a deep red by now. It was acidified with 10% HCl and extracted 2 x 150 mL DCM. The combined DCM extracts were dried over Na2SO4 and analyzed via GC/MS:

- N-formylamphetamine (48.20%)
- phenyl-2-propanoxime (17.88%)
- phenyl-2-propanone (5.94%)
- amphetamine-P2P imine (5.96%)

Also detected (in trace amounts): phenyl-2-nitropropane, amphetamine.

The aqueous layer was made alkaline by addition of KOH and extracted with 3 x 100 mL DCM. After evaporation of the solvent, a yellowish oil remained. Weight: 11.1 g amphetamine freebase. GC/MS analysis indicated the presence of phenyl-2-propanoxime and amphetamine-P2P imine, but their joint AREA% counted for less than 2%. The "missing" AREA% is taken by amphetamine.
Neutralizing amphetamine by 0.5 mol eq concentrated H2SO4 in two times its volume IPA. Some IPA and ether added after complete addition of the sulfuric acid. Crystals give a fairly pure look...

Comments & Additional Information

N-[2-(1-phenylpropyl)]-ethylidenimine

Where the fuck does this come from? This substance is reported to be found when amphetamine is dissolved in EtOH (it has m/z 70 - N-ethyl, like MDEA, has m/z 72). However, I did not use EtOH as solvent, but IPA. Contamination from the IPA? Possible, but unlikely (certainly since GC/FID did not indicate its presence when analyzed). However, there is something else that bothers me: amphetamine-benzaldehyde imine. This imine is formed by condensing amphetamine with benzaldehyde, an impurity that often is found in nitro-related reductions (concerning PEAs). But benzaldehyde? Yes, could be an impurity from the initial synthesis step, but I still have difficulties believing that this substance has survived two recrystallizations and NaBH4. Yes, there probably are some molecules of benzaldehyde still wandering around from the initial step, but it seems to much to be true. However, coming back to the "EtOH-artifact"... where does EtOH come from? Nowhere... The artifact is formed by condensation of P2P (also present as impurity) and ethylamine. Ethylamine? Yes, ethylamine, which originates from nitroethane. You see, I suspect that phenyl-2-nitropropene is partially hydrolyzed in benzaldehyde and nitroethane, after which nitroethane is reduced to ethylamine and benzaldehyde condensed with amphetamine. I have no other explanation for the presence of this artifact.

High mol eq of NaBH4 and Zn

You might notice that I use more NaBH4 and Zn than has been reported. However, using only a slight excess of sodium borohydride resulted in much unreacted phenyl-2-nitropropene. The latter disturbs your reaction in the Zn/HCOOH mediated reduction of phenyl-2-nitropropane. The nitropropene is reduced to phenyl-2-aminopropene. Sounds good, no? No! This compound will tautomerize and hydrolyze in an acidic environment (clearly present) and result in phenyl-2-propanone. This is a side reaction which is present in LAH reductions of phenyl-2-nitropropene as well. However, I believe that this side reaction has to be minimized (since P2P can condense with amphetamine), hence the excess of sodium borohydride.
I also opted for a large excess of Zn. It seemed to me that their was still alot of phenyl-2-propanoxime left, which usually indicates an incomplete reduction reaction. Since Zn is rather cheap, I just threw in 10 mol eq. As you can see in my results, there is a marked difference in yield (A: 2.7 g oil from 50 mmol phenyl-2-nitropropene, impure amphetamine - B: 11.1 g oil from 150 mmol phenyl-2-nitropropene, rather pure amphetamine)

Compared to LAH

I haven't performed the reduction of phenyl-2-nitropropene with LAH myself, but the literature describes that large excesses of LAH have to be used or phenyl-2-propanoxime will be the major substance (and NOT amphetamine!). Considering the price and availability of LAH, I guess it is time to wave LAH goodbye. Bye bye...


Bandil

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GC_MS> Yes, that's sweet work 8-) So you...
« Reply #59 on: October 21, 2003, 02:55:00 PM »
GC_MS>
Yes, that's sweet work  8)  So you got a 56% yield in the end right? That's not to shabby all things taken in account.

So the final verdict is 2 molar borohydride per mole of substrate?

Superb work!

Regards
Bandil