Author Topic: Novel high-yielding C=C reduction of nitrostyrenes  (Read 14902 times)

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Barium

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Novel high-yielding C=C reduction of nitrostyrenes
« on: April 12, 2003, 01:35:00 PM »
The reduction of the double bond in nitrostyrenes has been a great source of pain for many researchers. It has traditionally been reduced by various metal borohydrides in yields varying from bad to great. The high-yielding methods has relied on huge excess of reducing agent, and in some instances huge amounts of solvents. Thus making these methods somewhat unattractive despite the good yields. Phase transfer catalysis (PTC) can be used to transfer reagents (or substrates) from a phase where it is soluble to a phase where it is insoluble. Using PTC a reaction can take place in a solvent in which it normally couldn't.


General method for C=C reduction of nitrostyrenes

To 25 ml toluene in a 250 ml roundbottom flask equipped with a magnetic stirbar is added 500 mg Aliquat 336 [1] and 20,9 g (100 mmol) 2,4-dimethoxy-beta-nitrostyrene followed by a solution of 4,2 g (110 mmol) NaBH4 in 15 ml water containing 25 mg NaOH [2]. The mixture is violently stirred [3] for 1,5 hours while the temperature is kept at 25°C. The nitrostyrene gradually dissolves and the color changes from a dark yellow to a pale yellow as the reaction pregress. The color change is complete after about one hour but the reaction is allowed to go to completion by stirring for another 30 minutes.
The stirring is stopped and the mixture is transferred to a separatory funnel when the phases has separated the lower aqueous phase is removed and the organic phase is washed once with water and once with 25 ml water containing 2 ml GAA. The toluene is stripped of in a rotovap leaving a clear yellow oil weighing 21 g. 500 mg PTC was added so the weight of 1-(2,4-dimethoxyphenyl)-2-nitroethane is 20,5 g (97%).


[1] 500 mg Aliquat 336 is 1,2 mmol. The amount of PTC can be 1-5 mol % with little change in reaction time.
[2] NaOH is added to minimise the decomposition of the borohydride which otherwise starts as soon as the borohydride is dissolved in water.
[3] The two pahse mixture must be violently stirred, preferably a emulsion should be formed, in order to bring the phases in intimate contact.

Other solvents beside toluene can also be used. DCM is commonly used together with Aliquat 336 but pratically any water-immiscible organic solvent with which the substrate, product or reagent does not react can be used. The presense of PTC in the product does not disturb most further reductions of the nitro group. The pure nitroalkane can be isolated by vacuum distillation.

The following nitrostyrenes has been reduced with this method.

Phenyl-2-nitroethene (94%)
1-(4-Methoxyphenyl)-2-nitroethene (95%)
1-(2,5-Dimethoxyphenyl)-2-nitroethene (97%)
1-(2,4,5-Trimethoxyphenyl)-2-nitroethene (98%)
Phenyl-2-nitropropene (98%)
1-(2-Methoxyphenyl)-2-nitropropene (97%)
1-(2,5-Dimethoxyphenyl)-2-nitropropene (98%)
1-(2,4,5-Trimethoxyphenyl)-2-nitropropene (98%)


SpicyBrown

  • Guest
Excellent!
« Reply #1 on: April 12, 2003, 02:06:00 PM »
Barium,

This is most excellent! Have you subjected any of the nitroethane products from this alkene reduction to CTH or other nitro reducing reactions?

And.. Where DO you find the time to get all of this experimental work done?  :)

-SpicyBrown

Chimimanie

  • Guest
Many many thanx Barium
« Reply #2 on: April 12, 2003, 02:33:00 PM »
This is absolutely GREAT! 8)  ;D

I like to not use big amount of solvents and this reduction use so little, plain ol' toluene is very cheap, this reduction is so great!

BTW, does 25 ml of toluene dissolve the nitrostyrene, or is it a suspension?

You always amaze me, barium

Chimimanie  :)

Barium

  • Guest
SB: Yes I have. The PTC is of no problem if...
« Reply #3 on: April 12, 2003, 03:21:00 PM »
SB: Yes I have. The PTC is of no problem if the KCOOH/IPA/Pd-C system is used to reduce the nitro group.

C: It is a suspension at first then it becomes a solution as the reaction progress.


Greensnake

  • Guest
Great, Barium. One question though: ...
« Reply #4 on: April 12, 2003, 05:41:00 PM »
Great, Barium.

One question though:

>solution of 4,2 g (110 mmol) NaBH4 in 15 ml water containing 25 mg NaOH [2].

Is necessary amount of NaOH really 25 mg (less than 1 mmol) ?

pHarmacist

  • Guest
great!
« Reply #5 on: April 12, 2003, 05:58:00 PM »
It's nice to log on hive and see this kind of work. Who else can do stuff like this other than Barium? Barium, do you have any refs on this? Nothing more to say - Barium all the way!


Megatherium

  • Guest
The toluene is stripped of in a rotovap ...
« Reply #6 on: April 12, 2003, 08:11:00 PM »
The toluene is stripped of in a rotovap leaving a clear yellow oil weighing 21 g. 500 mg PTC was added so the weight of 1-(2,4-dimethoxyphenyl)-2-nitroethene is 20,5 g (97%).

1-(2,4-dimethoxyphenyl)-2-nitroethane

cattleprodder

  • Guest
Dear Barium.
« Reply #7 on: April 13, 2003, 09:08:00 AM »
Would you at least mind giving us some trip reports, specifically with the 2,4-dimethoxyamphetamine.  Thanx.

Barium

  • Guest
Reply
« Reply #8 on: April 13, 2003, 11:50:00 AM »
Greensnake:
Check [2] for the explanation why such a small amount NaOH is added.

pH: I have never seen anything published reminding of this method for reducing nitrostyrenes. When I read up on PTC some time ago I remember seeing something about aqueous borohydride behaving very well under PTC conditions. Then it was just a matter of make a few trials and then optimizing the method.

Mega: Thank you. I missed that one completely  :-[
   
cattle. Ever heard of PIHKAL? Read it. You'll be amazed of what you can find in there.


moo

  • Guest
Hats off
« Reply #9 on: April 13, 2003, 02:22:00 PM »
So this is completely your own work? Impressive... It might not be a great effort to you, but it sure is great for the Hive. I hope that someday there will be a wave of educated bees who got their first spark here and decided pay their debts to the Hive in the form of research. ;)

GC_MS

  • Guest
Some notes
« Reply #10 on: April 25, 2003, 10:10:00 AM »
1. DCM indeed works as well as toluene does, but be sure to use external cooling! I tried the procedure small-scaled, and a water-filled beaker was sufficient. I also tried the reaction without external heating, and the DCM evaporated completely. Although I could predict this, it was an entertaining view to see a RB flask being filled with foam  :)
2. The PTC does not interfere with the Zn/HCOOH reduction system. Might be a cheaper alternative for Pd/C  ;)

A write-up will follow next week. First, there is some bioassay-ing to do!


GC_MS

  • Guest
Where does this impurity come from?
« Reply #11 on: June 11, 2003, 02:30:00 PM »
I have been trying this method alot on p-methoxyphenyl-2-nitropropene. I am trying to find a good and cheap method to reduce the aliphatic nitro to the amine. Anisaldehyde is inexpensive, so I can toy around without wasting much valuable precursor.
I have screened the 4-methoxyphenylnitropropane reaction mixture with GC/MS several times, and I always noted the presence of an impurity which I believed to be 4-methoxyphenyl-2-propanone. During the night, I quickly performed a performic anethole oxidation to synthesize the ketone and compare the retention time/mass spectrum. There was a 99% match...
Now, there is no need to panic, no need at all. The GC peak area of the ketone amounts only 0.3%, but can still be found and identified.
Question: how does the ketone end up here? Might be Nef-related, but I thought you needed an acidic reaction environment for that. Any ideas?


Barium

  • Guest
Hmm
« Reply #12 on: June 11, 2003, 03:51:00 PM »
That's interesting, very interesting. For a nef reaction to occur the nitropropene has to be reduced to the nitropropane. So how is it reduced then? Can this side reaction occur due to some impurity in the nitroethane? Imagine is one could find the right conditions to make this ketone formation the main reaction.

Edit

What in God's name was I thinking of when I wrote the above? Nitrostyrene formation apparently. I'll go away and put on the silly hat for a while.  :-[  :-[

Interesting to see the nef reaction occurring under the alkaline conditions here. I wonder if this simple manipulation would be fruitful to make the ketone?

First the nitroalkene is reduced as usual. When the reduction is complete the excess borohydride is destroyed with dilute acetic acid. Then slightly more than one molar equivalent NaOH is added to create the sodium salt of the nitropropane which will move to the water phase. The toluene layer is then discarged. The aqueous solution is then added slowly to 2-3 molar equivalents dilute sulfuric acid. Now the nef reaction should take place. If so, the ketone (which should be visible as a oil) is simply extracted and distilled. I've never thought of this before. This must be tried soon


Rhodium

  • Guest
Another Nef variation
« Reply #13 on: June 12, 2003, 07:25:00 PM »
Another Nef variation:

https://www.thevespiary.org/rhodium/Rhodium/chemistry/phenylacetone.html#p2np

- works okay for P2P, but for substituted nitropropenes the oxidation goes too far, forming aldehydes and acids...

Barium

  • Guest
Ketone formation by nef reaction
« Reply #14 on: June 12, 2003, 08:06:00 PM »
I tried the method I proposed above  :)

1-(2,4-Dimethoxyphenyl)-2-nitropropene, 6 g (27 mmol)
NaBH4, 1,2 g (32 mmol)
Aliquat 336
NaOH
Water
Toluene
Sulfuric acid

To a solution of 1,2 g sodium borohydride in 20 ml water containing 20 mg NaOH, I added 20 ml toluene, 6 g  1-(2,4-dimethoxyphenyl)-2-nitropropene and 0,5 g Aliquat 336. The mixture was violently stirred for 20 minutes at 30°C. The color had then changed from the initial dark yellow to nearly colorless. Dilute acetic acid was then added until gas evolution ceased and the aqueous phase discarged.

To the toluene solution of 1-(2,4-dimethoxyphenyl)-2-nitropropane and aliquat 336 was then added 2,5 molar equivalents NaOH (67 mmol, 2,7 g) dissolved in 20 ml water, and the mixture was then stirred violently for 20 minutes while the temperature was kept at 60°C. The toluene solution was then separated from the aqueous solution now containing the sodium salt of 1-(2,4-dimethoxyphenyl)-2-nitropropane. This aqueous solution was then added dropwise to diluted sulfuric acid (130 mmol, 12,7g in 100 ml water) with good stirring while the temperature was kept at 60° by heating.

The acidic solution became cloudy immediately upon adding the alkaline solution and some oily drops became apparent. I also noticed the ketone smell. When all alkaline solution was added the solution resembled milk with a yellow oil floating on the surface. The heating and stirring was continued for 10 minutes. This caused the milkiness to dissapear and gave a clear solution with the ketone floating on the surface. The ketone was isolated by extraction with toluene (2x20 ml), the combined extracts was dried over MgSO4 and the solvent removed by distillation under reduced pressure. This left 2,8 g 1-(2,4-dimethoxyphenyl)-2-propanone (14 mmol, 51%).


Higher yields can be achieved if more nitroalkane can be dragged out of the toluene solution, as I suspect there is still more left in there. But hey, it's a good start!!


Aurelius

  • Guest
Barium
« Reply #15 on: June 12, 2003, 08:50:00 PM »
Damn Barium, is there anything you haven't tried or experimented with? (excluding all sexual references :P )


Rhodium

  • Guest
Experienced experimenter
« Reply #16 on: June 12, 2003, 09:02:00 PM »
AFAIK, he has experimented with everything in both areas... Right, Ba?  ;)

Barium

  • Guest
Oh yes
« Reply #17 on: June 12, 2003, 09:03:00 PM »
Unfortunately I won't be able to do more than a fraction of all I would want to do. But I'll make damn sure I do what I can to be a major pain in the ass to the turds in the DEA. As for the sexual area: I'll do as much "research" as I can there too  ;)


Aurelius

  • Guest
Pain in the ass?
« Reply #18 on: June 12, 2003, 09:14:00 PM »
Now, is that something that you regularly do?  :o

got some people that'd like you. :P


GC_MS

  • Guest
tsss....
« Reply #19 on: June 12, 2003, 10:28:00 PM »
WANTED: Hive chick for never-ending lovemaking (in a rather erotic/perv way of acting) under the influence of GC_MS's Laboratory Products...  :(

Barium: How about evaporating the toluene and taking up the residue in NaOH solution? Or am I missing something obvious  ::) ?


hCiLdOdUeDn

  • Guest
Barium....
« Reply #20 on: June 12, 2003, 10:53:00 PM »
Will this procedure (Ketone formation by nef reaction) work with MD2NP -> MDP2P?

I am VERY interested in that.

Thanks for all your hard work~

Barium

  • Guest
MDP2P
« Reply #21 on: June 13, 2003, 01:17:00 PM »
I don't know if MDP2NP would be converted cleanly to MDP2P with this method, but I suspect that a decent yield can be achieved. Sulfuric acid is very gentle to the MD-bridge as opposed to the other mineral acids. My guess is that the reaction between the sodium salt of the nitroalkane and the acid should proceed in a way that the liberated nitrogen oxides is allowed to get in contact with the ketone or nitroalkane is little as possible. This should prevent oxidative destruction.


Rhodium

  • Guest
Nef Reaction Review
« Reply #22 on: June 23, 2003, 05:54:00 AM »
If you are looking for other Nef reaction variations, here ia a review article of the Nef Reaction:

Chem. Rev. 55, 137 (1955)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/nef.reaction.review.pdf)

GC_MS

  • Guest
Reverse Addition of LAH to Nitroölefins - A
« Reply #23 on: July 01, 2003, 10:13:00 AM »
The original text can be found on Rh's site:

J Am Chem Soc 74(7) (1952) 1837-1842

(https://www.thevespiary.org/rhodium/Rhodium/pdf/lah-nitroalkenes.reverse-addition.pdf). Thank you both Rh and Lego for offering me the requested text. As you both replied to my request within a period of time I was absent, I was unable to erase the request in time. Sorry...

[Contribution no 247 from the department of Organic Chemistry and Enzymology, Fordham University.]

Reverse Addition of Lithium Aluminium Hydride to Nitroölefins



by RT Gilsdorf 1 and FF Nord


The reverse addition of lithium aluminium hydride (LAH) to 1-phenyl-2-nitropropene-1 was studied in detail in order to correlate this method with those previously recorded in the literature for the reduction of nitroölefins. A variety of products was isolated by varying the reaction temperature and the ratio of reactants. Among them was 1-phenyl-2-nitropropane, arising from the selective reduction of the double bond. By employing acidic hydrolysis of the intermediary organometallic complex, phenylacetone was obtained via a modified Nef reaction. Several other alpha-aryl ketones were similarly prepared. A study on the reverse addition of LAH to omega-nitrostyrene, led to the development of a novel method of converting benzaldehyde to its next higher homolog.


A. Reduction of 1-Phenyl-2-Nitropropene-1



Introduction

It has been shown 2,3 that when compounds of the type ArCH=CRX, where X is a polar group such as CHO, COOH or NO2, are treated with LAH via normal addition, the double bond, as well as the functional group, is reduced. However experiments 4 on the reverse addition of the above reagent to cinnamaldehyde demonstrated that the carbonyl function could be selectively reduced by such a method. In view of the above findings and of the fact that nitroölefins prepared from aromatic aldehydes conform to the type ArCH=CRX, where X is NO2, the reverse addition of LAH to nitroölefins was studied, as a continuation of our earlier investigation, 3 to correlate this method with those previously reported 5 for the reduction of nitroölefins. In these latter cases a wide variety of products has been obtained but at no time has any uncondensed 6 beta-aryl nitroalkane been isolated.
The nitroölefins chosen for study was 1-phenyl-2-nitropropene-1.

Experimental

Reduction of 1-phenyl-2-nitropropene-1 to beta-phenylisopropylamine and N-(beta-phenylisopropyl)-hydroxylamine. - In a three-necked two-liter flask equipped with a mechanical stirrer, dropping funnel and a condenser through which was suspended a low temperature thermometer (openings protected with calcium chloride tubes), a solution of 12.2 g (0.075 mole) of 1-phenyl-2-nitropropene-1 in 300 mL of absolute ether was cooled to below -30°C with an acetone-dry ice bath. During rapid stirring, a solution of 4.25 g (0.112 mole, the calculated amount for the reduction of the nitro group) of LAH in 100 mL of absolute ether, was added at such a rate that the temperature of the reaction mixture was maintained between -30°C and -40°C. Exothermic reaction progressed during the addition and the color of the nitroölefin was discharged. The temperature in the reaction flask was then allowed to fall below -40°C, the freezing bath was removed and the temperature allowed to rise to 15°C. Hydrolysis was carried out with 400 mL of 20% aqueous sodium potassium tartrate. The addition of the first few drops of this solution caused slight reaction indicating that the hydride had not been completely utilized. The qaueous layer was extracted with two additional 50-mL portions of ether and the combined ethereal extracts, after drying over Drierite, yielded, on rectification, 4.4 g (44%) of beta-phenylisopropylamine, bp 72-74°C (4.0 mm) and 2.6 g (23%) of N-(beta-phenylisopropyl)-hydroxylamine, bp 116-118°C (4.0 mm). The latter substance was solidified. Recrystallization from light petroleum ether afforded a white crystalline solid, mp 63-64°C. Anal.: Calcd for C9H13NO: C, 71.42; H, 8.66. Found: C, 71.69; H, 8.42.
The beta-phenylisopropylamine isolated was characterized as its hydrochloride and phenylthioreide: the hygroscopic hydrochloride, prepared by bubbling anhydrous hydrogen chloride through a solution of the amine in absolute ether, after recrystallization from an absolute alcohol-ether combination, had a mp of 147-148°C. In the literature 7, the mp is listed as 145-147°C. Anal.: Calcd for C9H14ClN: N, 8.15. Found: N, 8.30. The phenylthioreide, prepared in the usual way 8, had a mp of 131.5-132.5°C after recrystallization from alcohol. Anal.: Calcd for C14H18N2S: C, 71.07; H, 6.71. Found: C, 71.30; H, 6.38.
The previously unreported N-(beta-phenylisopropyl)-hydroxylamine readily reduced Tollens reagent at room temperature. It had the same melting point as, and did not depress the melting point of, N-(beta-phenylisopropyl)-hydroxylamine synthesized according to an earlier method 9: A mixture of 1.5 g (0.01 mole) of phenylacetoxime dissolved in 25 mL of 70% alcohol containing 0.365 g of HCl and 0.1 g of platinum black was shaken under hydrogen until 0.01 mole was taken up. The catalyst was removed by filtration. The volume of the filtrate was increased to 75 mL with water and extracted with ether. The aqueous portion was then neutralized with aqueous sodium bicarbonate and the precipitate was collected. On recrystallization from light petroleum ether, there was obtained 0.64 g (42%) of N-(beta-phenylisopropyl)-hydroxylamine, mp 63-64°C, which was not depressed when mixed with the sample obtained from the reverse addition of LAH to 1-phenyl-2-nitropropene-1.

N-(beta-phenylisopropyl)-hydroxylamine oxalate. - When 0.18 g (0.02 mole) of oxalic acid dissolved in 10 mL of absolute ether, was added, with stirring, to a solution of 0.6 g (0.04 mole) of N-(beta-phenylisopropyl)-hydroxylamine in 10 mL of absolute ether, there was obtained a white precipitate of the neutral oxalate which, on recrystallization from an absolute methanol-ether mixture, melted at 175-176°C. Anal.: Calcd for C20H28N2O6: C, 61.21; H, 7.19. Found: C, 61.30; H, 6.99.

N-(beta-phenylisopropyl)-p-nitrophenylnitrone. - The procedure employed here was essentially reported previously. 10 There were mixed together 0.3 g (0.02 mole) N-(beta-phenylisopropyl)-hydroxylamine dissolved in 6 mL of absolute alcohol and 0.3 g (0.02 mole) p-nitrobenzaldehyde in 10 mL of absolute alcohol. After standing 24 hours, the alcohol was removed under reduced pressure and the residue was recrystallized from absolute ether (freezer). There was thus obtained a light yellow crystalline product, mp 119-120°C. Anal.: Calcd for C16H16N2O3: C, 67.59; H, 5.67. Found: C, 67.45; H, 5.67.

beta-Phenylisopropylamine. - A solution of 6.0 g (0.04 mole) of N-(beta-phenylisopropyl)-hydroxylamine in 80 mL of absolute ether was treated with 1.9 g (0.05 mole) of LAH dissolved in 150 mL of absolute ether in the usual manner and refluxed for an additional hour. After cooling, a sample of the reaction mixture gave a positive Gilman-Schultz color test 20 indicating an excess of the hydride. Hydrolysis was carried out with 400 mL of 20% aqueous sodium potassium tartrate and after separation of the layers, the aqueous portion was extracted with two additional 75-mL volumes of ether. Rectification afforded 2.0 g (37%) of beta-phenylisopropylamine, bp 72-74°C (4.0 mm), identified by is phenylthioreide.

N-(beta-phenylisopropyl)-hydroxylamine and phenylacetoxime. - When 2.13 g (0.056 mole, half the amount necessary for the reduction of the nitro group) dissolved in 100 mL of absolute ether, was added to 12.2 g (0.075 mole) of 1-phenyl-2-nitropropene-1 in 300 mL of absolute ether at -30° to -40°C, as before, and after hydrolysis with 20% aqueous sodium potassium tartrate, there were obtained 1.1 g (8%) of beta-phenylisopropylamine, bp 72-74°C (4.0 mm), and 5.6 g of a fraction 11, bp 116-118°C (4.0 mm), which failed to reach rigid solidity after 2 days in a vacuum desiccator over sulfuric acid. A portion of this material was treated with warm petroleum ether (bp 30-60°C). After decantation petroleum ether, on cooling, yielded crystalline N-(beta-phenylisopropyl)-hydroxylamine.
Another aliquot of the higher boiling fraction was dissolved in ether and shaken with an excess of cold 1 N HCl to remove the hydroxylamine derivative. The ether layer was then washed well with water and dried over Drierite. Removal of the ether on the steam-bath afforded an oil which on chilling and scraping, solidified. Recrystallization from petroleum ether (bp 60-75°C) yielded phenylacetoxime of mp 68.5-70°C. In the literature 12 the mp is recorded as 68-70°C. Anal.: Calcd. for C9H11NO: C, 72.45; H, 7.43. Found: C, 72.40; H, 7.24.
A third aliquot of the higher boiling fraction was weighed (2.0 g) and dissolved in 100 mL of 6 N HCl. Steam was passed through the solution until phenylacetone (identified as its semicarbazone) ceased to be distilled. The clear acidic hydrolytic solution was made basic with 4 N sodium hydroxide, afforiding 1.36 g of N-(beta-isopropyl)-hydroxylamine. Assuming that the ketone was quantitatively hydrolyzed and that there was no loss of the hydroxylamine in handling, this experiment allows the estimation of the ketoxime content of the mixture as being 32%. This corresponds to over-all yields of 8% beta-phenylisopropylamine, 16% phenylacetoxime and 34% N-(beta-phenylisopropyl)-hydroxylamine.

Action of 2,4-dinitrophenylhydrazine sulfate on phenylacetoxime. - When phenylacetoxime was treated with 2,4-dinitrophenylhydrazine sulfate in the usual manner 13, precipitation occurred immediately. Recrystallization from an ethyl acetate-alcohol mixture afforded orange crystals of mp 152.5-153.5°C which was not depressed when mixed with an authentic sample of the 2,4-dinitrophenylhydrazone of phenylacetone. This mp was originally reported as 155.5-156.5°C 14. Anal.: Calcd for C15H14N4O4: N, 17.83. Found: N, 17.70.

Phenylacetone (via phenylacetoxime). - A solution of 2.13 g (0.056 mole, half the amount necessary for the reduction of the nitro group) of LAH in 100 mL of absolute ether, was added to 12.2 g (0.075 mole) of 1-phenyl-2-nitropropene-1 in 300 mL of absolute ether, at -30° to -40°C , as above. After the temperature of the reaction mixture had been allowed to rise to 15°C, 300 mL of 6 N HCl was introduced to hydrolyze the intermediate organometallic complex. The layers were seperated and the ethereal layer was successively washed with two 100-mL volumes of 6 N HCl. The combined aqueous acidic portions were steam distilled. The distillate was extracted with the original ether layer and two additional 50-mL portions of ether. Rectification afforded 2.9 g (29%) of phenylacetone, bp 73-74°C (4.0 mm)
The 2,4-dinitrophenylhydrazone was prepared and recrystallized as previously indicated. Its mp was 152.5-153.5°C.
The semicarbazone was prepared according to the usual procedure 15. Recrystallization from 75% alcohol afforded a white crystalline product of mp 186-187°C. This mp was previously reported 16 as 187°C. Anal.: Calcd. for C10H13N3O: C, 62.80; H, 6.85. Found: C, 63.25; H, 6.61.

1-Phenyl-2-nitropropane. - A. LAH (0.855 g, 0.0225 mole, a 20% excess of the amount required for the reduction of the double bond) in 100 mL of absolute ether, was added to 12.2 g (0.075 mole) of 1-phenyl-2-nitropropene-1 in 300 mL of absolute ether at -40° to -50°C as described above. The organometallic complex was hydrolyzed with 20% aqueous sodium potassium tartrate. On rectification, there was obtained 4.7 g (38%) of 1-phenyl-2-nitropropane, bp 103-104°C (4.0 mm). Anal.: Calcd for C9H11O2: C, 65.43; H, 6.71. Found: C, 65.99; H, 6.69.
B. When the above experiment was repeated using as the hydrolytic agent the calculated amount of 1 N HCl which was introduced dropwise over the course of three quarters of an hour, 1.5 g (15%) of phenylacetone and 6.9 g (56%) of 1-phenyl-2-nitropropane were obtained.
1-Phenyl-2-nitropropane gave a definite blue-green coloration characteristic of the pseudo-nitroles produced by secondary nitro compounds when treated according to the conditions of the nitrous acid test. 17 The coloration was chloroform extractable. A similar test performed omitting the sodium nitrite, gave only a very faint green color.

beta-Phenylisopropylamine. - By the normal addition, 1.65 g (0.01 mole) of 1-phenyl-2-nitropropane in 50 mL of absolute ether, was treated with 0.68 g (0.018 mole, a 20% excess) of LAH in 70 mL of absolute ether. Hydrolysis was brought about by means of 150 mL of 20% aqueous sodium potassium tartrate. Upon distillation of the ethereal layer, there was obtained a small amount of oil which gave a phenylthioureide of mp 131.5-132.5°C which was not depressed when mixed with an analyzed sample of the phenylthioureide of beta-phenylisopropylamine.

Nef reaction 18 on 1-phenyl-2-nitropropane. - One-half of a gram of 1-phenyl-2-nitropropane was dissolved in 10 mL of aqueous solution containing 0.5 g of sodium hydroxide. This solution was added dropwise to a solution of 2.5 mL of concentrated sulfuric acid and 16 mL of water during rapid stirring and cooling with an ice-bath. An oil separated with the characteristic odor of phenylacetone. It was extracted with ether and after the removal of the ether, was treated with semicarbazide hydrochloride and sodium acetate in the usual manner for the preparation of a semicarbazone 15. In this way, there was obtained a white crystalline product, which, after recrystallization from 80% alcohol, had the same mp as, and did not depress the mp of, an authentic sample of the semicarbazone of phenylacetone (186-187°C).

Absorption data. The IR curves (Figs 2, 3, 4 - (refer to original text)) were obtained on a Perkin-Elmer 21-Double beam spectrophotometer using Nujol mulls of the samples.


GC_MS

  • Guest
second part...
« Reply #24 on: July 01, 2003, 10:37:00 AM »
Discussion

The experiments carried out on 1-phenyl-2-nitropropene-1 and its reductive derivatives are outlined in Figure 1 (refer to original text). These reactions demonstrated that the reduction was stepwise and capable of regulation so as to afford the amine, hydroxylamine derivative, oxime or nitroparaffin in various mixtures. While the formation of Complex I was undoubtedly the favored reaction at -40 to -50°C since the nitroparaffin, 1-phenyl-2-nitropropane, was obtained in 56% yields, and while some of Complex II must have been formed at -30 to -40°C to account for the phenylacetoxime isolated, neiter reaction has been proven as being mutually exclusive of each other at the temperatures involved.
The preparation of its hydrochloride and phenylisothioureide served to characterize the beta-phenylisopropylamine formed. The identity of the N-(beta-phenylisopropyl)-hydroxylamine was proven by its ready reduction of Tollens reagent, the preparation of its oxalate, the nitrone formation and by the fact that it did not depress the melting point of an authentic sample prepared according to the method of Vavon and Crajcinovic. 9 The phenylacetoxime was characterized by virtue of its melting point, hydrolysis to phenylacetone and conversion to the 2,4-dinitrophenylhydrazone. The blue-green coloration, manifested by pseudonitroles which are formed by secondary nitro compounds under the conditions of the V Meyer nitrous acid test 17, its reduction to beta-phenylisopropylamine with LAH and conversion to phenylacetone when treated according to the conditions of the Nef reaction, established the structure of 1-phenyl-2-nitropropane.
The reduction of N-(beta-phenylisopropyl)-hydroxylamine to beta-phenylisopropylamine with LAH is novel since we have been able to find no report in the literature on the reduction of a hydroxylamine derivative with this reagent.
It is noteworthy that the phenylacetoxime and N-(beta-phenylisopropyl)-hydroxylamine distilled together in the fraction obtained at 116-118°C (4.0 mm) The fact that the distillate failed to crystallize readily, led to the assumption that it might be a mixture. This contention was verified by the chemical separation of the components and supported by the IR absorption data. Curve H was obtained for N-(beta-phenylisopropyl)-hydroxylamine. It is noticed that there is a strong absorption band at 1108 cm-1 which is absent in curve O. Curve O, that of phenylacetoxime, demonstrateds absorption at 1666 cm-1 assignable to the C=N bond of the oxime group. Curve D, that of the reaction distillate, shows absorption at both the above frequencies and, in general, has all the peaks present in curves H and O.
The major portion of the phenylacetone formed when one half the amount of LAH was added at -30 to -40°C, probably arose from the acidic hydrolysis of the oxime which, itself, was isolated by applying hydrolysis with 20% aqueous sodium potassium tartrate.
The conversion of the nitroölefin to the corresponding nitroparaffin, 1-phenyl-2-nitropropane, is novel since no similar reduction, i.e., the selective reduction of the double bond, has been reported in the aryl series without condensation 6.
The fact that either 1-phenyl-2-nitropropane or phenylacetone can be isolated from the same reaction mixture depending on the type of hydrolysis, indicates that the mechanism of the ketone formation when the lower concentration of hydride was used, is a modified Nef reaction. The transitory blue color which is characteristic of the Nef reaction, and which was observed during the hydrolysis, supports this contention.
In view of the findings by Hochstein and Brown 4 on the reduction of cinnamyl alcohol to hydrocinnamyl alcohol, it is possible that the reduction of 1-phenyl-2-nitropropene-1 to 1-phenyl-2-nitropropane involves only the double bond 19 and is effected by 0.25 mole of LAH per mole of nitroölefin.


GC_MS

  • Guest
Reverse Addition of LAH to Nitroölefins - B
« Reply #25 on: July 01, 2003, 03:01:00 PM »
B. Synthesis of other alpha-aryl ketones


Experimental

Preparation of other alpha-aryl ketones and N-(beta-aralkyl)-hydroxylamines. - By treating the corresponding nitroolefins with a 20% excess of the amount of LAH necessary for the reduction of the double bond via reverse addition at -40 to -50°C, followed by hydrolysis by means of the rapid introduction of 400 mL of 6 N HCl, and steam distillation of the aqueous phase, the ketones, listed in Table I (cf original text), were prepared. The corresponding N-(beta-aralkyl)-hydroxylamines were isolated in low yields by making the aqueous acidic solution through which the steam had been passed, alkaline and extracting with ether.

1-o-Chlorophenyl-2-nitropropene-1. - A. Modified Knoevenagel-Walter Synthesis. There were refluxed together for 8 hours, 28.1 g (0.2 mole) of o-chlorobenzaldehyde, 15.0 g (0.2 mole) of nitroethane, 1.74 g (0.02 mole) of n-amylamine and 30 mL of absolute alcohol. On cooling, the mixture was stored in the refrigerator until the precipitation was complete. The mixture was filtered and the precipitate washed with a few mL of absolute alcohol. There were thus obtained 20.0 g of 1-o-chlorophenyl-2-nitropropene-1. An additional amount of 2.0 g was obtained by concentration of the filtrate and washings, bringing the total yield to 56%. B. Knoevenagel-Walter synthesis. 21 - When the same quantities of the above reagents were mixed and allowed to stand at room temperature for 2 weeks, and the product was isolated in the same manner, there was obtained a total yield of 24.1 g (61%) of 1-o-chlorophenyl-2-nitropropene-1. Recrystallization from absolute ethanol produced bright yellow crystals, mp 40°C. Anal.: Calcd for C9H8ClNO: C, 55.00; H, 4.08. Found: C, 54.98; H, 3.88.

2-Thienylacetoxime. - When 2-thienylacetone was treated in the usual manner 22 for the preparation of an oxime there was obtained, on recrystallization from petroleum ether (bp 60-75°C), a white crystalline product, mp 91-92°C, which was not depressed when mixed with a sample prepared according to the method of Bouveault and Wahl 2e by the action of aluminium amalgam on 1-(2-thienyl)-2-nitropropene-1.

Discussion

The preparation of the ketones listed in Table I demonstrated the general applicability of this method of synthesizng carbonyl compounds from beta-arylnitroölefins. In general, the yields were good, the lowest (43%) being obtained from the relatively unstable 1-(2-thienyl)-2-nitropropene-1. The ketones are assumed to arise via the same mechanism as did phenylacetone in the previous experiment, i.e. by a modified Nef reaction after the selective reduction of the double bond of the nitroalkene.
The substituted hydroxylamines listed in Table I all readily reduced Tollens reagent at room temperature.
The experiments on the synthesis of the previously unreported 1-o-chlorophenyl-2-nitropropene-1 showed a slightly higher yield for the Knoevenagel-Walter synthesis (61% vs 56%) as compared to the much shorter reaction time of the modified Knoevenagel-Walter synthesis (8 hours vs 14 days).
The authenticity of the oxime prepared from 2-thienylacetone was proven by means of the mixed melting point determination with the sample obtained by the reduction of 1-(2-thienyl)-2-nitropropene-1 with aluminum amalgam.


C. Reduction of omega-nitrostyrene


Experimental

Reduction of omega-nitrostyrene to beta-phenylethylamine, N-(beta-phenylethyl)-hydroxylamine and phenylacetaldoxime. - When 2.13 g (0.056 mole, half the amount necessary for the reduction of the nitro group) of LAH dissolved in 100 mL of absolute ether, was added to 11.2 g (0.075 mole) of omega-nitrostyrene at -30 to -40°C as before and after hydrolysis with 20% aqueous sodium potassium tartrate, a mixture of products was obtained. Upon distillation, there was isolated 0.5 g (6%) of beta-phenylethylamine, bp 72-77°C (6.0 mm). The residue 11b in the distilling flask was dissolved in ether and extracted with an excess of 1 N HCl. After removal of the ether by distillation there was obtained 1.6 g (16%) of phenylacetaldoxime which melted at 97-98°C after recrystallization from petroleum ether (bp 60-75°C). The recorded 23 mp is 97-99°C. Anal.: Calcd for C8H9NO: C, 71.09; H, 6.71. Found: C, 71.03; H, 6.45. Neutralization of the acidic washings with dilute aqueous sodium carbonate afforded 3.4 g (33%) of N-(beta-phenylethyl)-hydroxylamine. After recrystallization from light petroleum ether, it melted at 83-84°C. Anal.: Calcd for C8H11NO: C, 70.04; H, 6.71. Found: C, 70.12; H, 7.93.

Phenylthioureide of beta-phenylethylamine. - This white crystalline substance was synthesized according to the previously utilized procedure 4. Its mp was 110-110.5°C. The mp was previously reported 24 as 111°C. Anal.: Calcd for C15H16N2S: C, 70.27; H, 6.29. Found: C, 70.38; H, 6.10.

beta-Phenylethylamine hydrochloride. - This compound was prepared by the previously described procedure. It was recrystallized from an absolute alcohol-ether combination. It mp was 215-217°C. Literature 25 records the mp as 217°C.

Action of 2,4-dinitrophenylhydrazine sulfate on phenylacetaldoxime. - When 0.5 g of phenylacetaldoxime was treated according to the prveiously utilized procedure for the preparation of a 2,4-dinitrophenylhydrazone, there was obtained an orange crystalline solid, mp 121-121.5°C, which did not depress the mp of an authentic sample of the 2,4-dinitrophenylhydrazone of phenylacetaldehyde.

N-(beta-phenylethyl)-p-nitrophenylnitrone. - When 2.7 g (0.02 mole) of N-(beta-phenylethyl)-hydroxylamine dissolved in 6 mL of absolute alcohol, and 0.3 g (0.02 mole) of p-nitrobenzaldehyde dissolved in 10 mL of absolute alcohol had been mixed together, the solution started to deposit yellow crystals after 2 hours standing at room temperature. After 24 hours the precipitate was filtered and recrystallized from absolute alcohol. In this way there was obtained a yellow crystalline solid, mp 157-158°C. Anal.: Calcd for C15H14N2O3: C, 66.65; H, 5.22. Found: C, 66.75; H, 5.29.

N-(beta-phenylethyl)-hydroxylamine oxalate. - The neutral oxalate was prepared as previously described and recrystallized from a methanol-ether combination. Its mp was 165.5-167°C with decomposition. Anal.: Calcd for C18H24N2O6: C, 59.30; H, 6.59. Found: C, 59.85; H, 6.49.

Phenylacetaldehyde. - When 0.855 g (0.0225 mole, a 20% excess for the reduction of the double bond) of LAH was treated with 11.2 g (0.075 mole) of omega-nitrostyrene via reverse addition at -40 to -50°C and hydrolysis was brought about by 400 mL of 6 N HCl introduced rapidly, there was obtained after steam distillation of the acidic hydrolytic mixture and rectification, 0 to 0.46 g (0-5%) of phenylacetaldehyde, bp 61-65°C (5.0 mm).
When hydrolysis of the intermediate organometallic complex was effected with the calculated amount of 1 N HCl, added slowly, the ether layer afforded a crude yellow oil which, when treated according to the nitrous acid test, gave an orange-red coloration comparable in shade and intensity to that given by 1-nitrobutane when similarly treated.
The crude oil was then triturated with a solution of 4.0 g of sodium hydroxide in 75 mL of water to yield a dispersion which, when added to an ice cold solution of 12.5 mL of sulfuric acid in 80 mL of water during rapid stirring (Nef reaction), allowed the separation of 0.92 g (10%) of phenylacetaldehyde, bp 63-64°C (5.0 mm).
The methone derivative of phenylacetaldehyde was prepared by the usual method. 26 Its mp was 164-165°C, the same as reported previously. 27
The 2,4-dinitrophenylhydrazone of phenylacetaldehyde was prepared as before. Its mp was 121-121.5°C which was not depressed when mixed with an authentic sample.

Discussion

In general, the experiments on the reduction of omega-nitrostyrene via the reverse addition of LAH indicated that it behaved similarly to 1-phenyl-2-nitropropene-1. In most cases, the same derivatives were prepared to characterize the various products.
However, a dissimilarity showed itself in the synthesis of the carbonyl derivative insofar as the yield of phenylacetaldehyde was very low. It is believed that here the mechanism of the reduction is still comparable while the ease of hydrolysis differs. The facts that a positive nitrous acid test was obtained for a primary nitro group and that the yield of phenylacetaldehyde marks the first reliable synthesis of the next higher homolog of benzaldehyde via omega-nitrostyrene, since the reported reduction of omega-nitrostyrene to the aldoxime followed by hydrolysis to the aldehyde, 28 has been described as being incapable of repetition. 29.


References


1. condensed from a part of the dissertation submitted to the Graduate Faculty of Fordham University in partial fulfillment for the degree of Doctor of Philosophy.
2. (a) RF Nystrom e.a. JACS 69, 1197 (1947) (b) 69, 2548 (1947) (c) 70, 3738 (1948).
3. RT Gilsdorf e.a. JOC 15, 807 (1950).
4. FA Hochstein e.a. JACS 70, 3484 (1948).
5. (a) G Alles. ibid. 54, 271 (1942) (b) O Schales. Ber 68, 1579 (1935) (c) J Kindler e.a. Ann 511, 209 (1934) (d) B Reichert e.a. Arch Pharm 273, 265 (1935) (e) L Beauvault e.a. CR 134, 1145 (1902) (f) A Sonn e.a. Ber 50, 1513 (1917) (g) H Cerf de Mauney. Bull Soc Chim [5] 7, 133 (1940) (h) EP Kohler e.a. JACS 43, 1281 (1923).
6. The reduction of omega-nitrostyrene to 2,3-diphenyl-1,4-dinitrobutane has been reported 5f.
7. DH Dey. JCS 18 (1930).
8. RL Shriner, RC Fuson. Identification of Organic Compounds", 3rd ed, J Wiley and Sons, Inc, NY 1948, p 206.
9. G Vavon e.a. Bull Soc Chim [4] 43, 231 (1928).
10. GW Watt e.a. JOC 8, 540 (1943).
11. (a) This fraction was incorrectly described as benzyl methyl ketimine in our preliminary communication, JACS 72, 4327 (1950). The hydrated trimer of the imine mentioned, actually was the hydroxylamine derivative; (b) similarly, a mixture of phenylacetaldoxime and N-(beta-phenylethyl)-hydroxylamine was mistaken for phenylacetaldimine and the compound erroneously described as the hydrated trimer of the aldimine, was actually the hydroxylamine derivative.
12. PW Neber e.a. Ann 449, 109 (1926).
13. RL Shriner, RC Fuson. Identification of Organic Compounds", 3rd ed, J Wiley and Sons, Inc, NY 1948, p 171.
14. WD McPhee e.a. JACS 66, 1132 (1944).
15. RL Shriner, RC Fuson. Identification of Organic Compounds", 3rd ed, J Wiley and Sons, Inc, NY 1948, p 170.
16. PA Levene e.a. J Biol Chem 90, 81 (1931).
17. V Meyer. Ann 175, 120 (1875).
18. HB Hass e.a. Chem Rev 32, 399 (1943).
19. It is also quite possible that the reduction may occur via a 1,4-addition especially in view of the polarity of the nitro group and of the fact that the reduction takes place at -40 to -50°C. It was reported 4 that the reduction of the double bond of cinnamyl alcohol proceeds slowly at room temperature after the rapid interaction of the polar alcoholic group with the hydride.
20. HB Hass e.a. JOC 15, 8 (1950).
21. E Knoevenagel e.a. Ber 37, 4502 (1902).
22. RL Shriner, RC Fuson. Identification of Organic Compounds", 3rd ed, J Wiley and Sons, Inc, NY 1948, p 202.
23. W Dollfus. Ber 25, 1917 (1892).
24. J von Braun e.a. Ber 45, 2188 (1912).
25. K Kindler,

Patent DE362714


26. EC Horning e.a. JOC 11, 93 (1946).
27. KH Lin e.a. JCS 2005 (1938)
28. L Bouveault e.a. Bull Soc Chim [3] 29, 518 (1903).
29. HB Hass e.a. Chem Rev 32, 399 (1943).


Chimimanie

  • Guest
Good Work
« Reply #26 on: July 01, 2003, 11:49:00 PM »
impressive to having posted all that GC,

thank you for the hard time  ;) .

GC_MS

  • Guest
Cuisiner avec GC/MS: la Soupe Stupéfiante
« Reply #27 on: July 03, 2003, 01:56:00 PM »
I have tried Ba's method, but usually in a more or less adapted way. I never added all nitrostyrene (NS) at once, as he did. Barium uses a small molar excess of NaBH4 in his procedure. Maybe the small molar excess is sufficient to bring the reaction to a good end, but it is not for the way I do it.

Ingredients: 50 mmol NS, 1.1 molar eq NaBH4, 0.3 g Aliquat 336, 25 mL toluene.

Procedure: The NaBH4 is weighed and dissolved in aqueous NaOH (I have a stock solution for this purpose, containing 0.4 g NaOH in 0.500 mL dH2O). This solution is added to a 250 mL RB flask containing 0.3 g Aliquat 336 and 25 mL toluene. The mixture is stirred vehemently for 5 minutes, after which the NS is added in portions. The rate of addition is determined by the colour of the reaction mixture. When adding the NS, the reaction mixture turns yellow. An exothermic reaction sets is and the colour becomes more or less colourless. When the reaction colour is colourless again, a new spoontip of NS crystals is dropped in. This way, the reaction temperature is kept under control as well. However, I noticed that the reaction mixture colour remained yellow once roughly 70-80% of the NS was added. When adding new NS crystals, there was no sizzling of the reaction mixture. My conclusion was that the NaBH4 was depleted. When adding an extra 0.5 molar eq NaBH4, the reaction continued smoothly. When all NS was added, the reaction was continued for 45 minutes and residual NaBH4 was neutralized with GAA. Workup according Ba's method resulted in a 86% yield of 4-methoxy-phenyl-2-nitropropane, which was a pale yellow oil. Addition of all Ns consumed 1.5-2 hours.

Repeating the experiment with 50 mmol phenyl-2-nitropropene and 2.0 molar eq NaBH4 resulted in a smoothly running reaction and there was no need to add extra NaBH4 during the reaction. Phenyl-2-nitropropane was obtained in 90% yield as very pale yellow oil. Addition of all NS consumed about 1.5 hours.

Identity has been checked with MS, and both nitroalkanes displayed M+ which were 2 amu higher then the M+ in the spectra of their nitroalkene analogues.


Sunlight

  • Guest
Have you tried it with 2,5 DMNS ?
« Reply #28 on: July 03, 2003, 02:35:00 PM »
Nitropropenes are less prone to dimerization. I've tried it with 2,5 DMNS in microscale and the TLC was not really good. It's not enough to conclude anything, I could fuck something.

GC_MS

  • Guest
hmm
« Reply #29 on: July 03, 2003, 02:50:00 PM »
I could fuck something

You aren't expecting me to reply on that, do you?  ;D


Sunlight

  • Guest
No, of course.
« Reply #30 on: July 03, 2003, 05:23:00 PM »
What I want to know is if you have tried it with nitrostyrenes.

LaBTop

  • Guest
Huh???
« Reply #31 on: July 04, 2003, 02:54:00 AM »
He tried it first with 50 mmol nitrostyrene (NS) and got a 86% yield of 4-methoxy-phenyl-2-nitropropane.
 
Then he repeated the reaction with phenyl-2-nitropropene and excess, better said, enough NaBH4 and got 90% yield of phenyl-2-nitropropane.

Who's making a typo here, GC_MS or Sunlight?  LT/  :)


Rhodium

  • Guest
No typo, just unclarity
« Reply #32 on: July 04, 2003, 03:36:00 AM »
Phenyl-2-nitropropene is a beta-methyl-substituted beta-nitrostyrene, so there is nothing wrong with calling nitropropenes nitrostyrenes (Shulgin does that all the time). However, Sunlight wants to know if it has been tried on plain nitrostyrenes (without that beta-methyl), as they are more prone to dimerization.

GC_MS

  • Guest
NS
« Reply #33 on: July 04, 2003, 08:20:00 AM »
NS = nitrostyrenes; phenyl-2-nitropropene = alfa-methyl-NS  :P

Sunlight, no, not tested (yet).


LaBTop

  • Guest
Nomenclature!
« Reply #34 on: July 05, 2003, 01:35:00 AM »
This once more indicates that we should restrict ourselfs to IUPAC or/and CAS nomenclature.
And include those nrs in important procedures, for the precursors and endproducts.

There must be one Hive-guideline for nomenclature, and we should discuss elsewhere which nomenclature we must follow :

http://www.acdlabs.com/iupac/nomenclature/

  Searchable!
The HTML version of IUPAC "Blue Book" Nomenclature of Organic Chemistry, Pergamon
Press, Oxford, 1979 and A Guide to IUPAC Nomenclature of Organic Compounds.
Description: Recommendations 1979 and 1993. Nicely organized and searchable.

http://people.ouc.bc.ca/woodcock/nomenclature/


Basic Organic Nomenclature, An Introduction.
Dave Woodcock ©1996,2000  Okanagan University College.

http://www.chem.qmul.ac.uk/iupac/ UP to DATE! IUPAC Chemical Nomenclature Searchable:

http://www.chem.qmul.ac.uk/iupac/search.html




IUPAC International Union of Pure and Applied Chemistry :
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http://www.iupac.org/


        :

http://www.iupac.org/general/FAQs.html


        :

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  : Search IUPAC.
GERMANY :

http://sunsite.informatik.rwth-aachen.de/iupac/


        :

http://sunsite.informatik.rwth-aachen.de/iupac/general/FAQs.html

  
UK      :

http://iupac.chemsoc.org/



Systematized Nomenclature of Medicine, better known as SNOMED® :

http://www.snomed.org/


Released in January 2002. SNOMED users include many leading organizations in the health care industry and health information technology field, from nationwide provider organizations and HMOs to pharmaceutical companies, Web portals and government agencies.


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:
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 = Regulated Chemicals Information:

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Opinions ? LT/


weedar

  • Guest
well
« Reply #35 on: July 08, 2003, 01:10:00 AM »
make own sticky thread for this, too important to bee hidden
inside an exciting thread like this.
(not implying that nomenclature is boring...)


Barium

  • Guest
Improvement
« Reply #36 on: July 27, 2003, 07:10:00 PM »
Even though it gives good yields I've never been completely happy with Aliquat 336 as PTC in this reduction. Finally the need of this PTC is no more and I'm happily singing a little tune.  :)

Reduction of 2,5-dimethoxy-beta-nitrostyrene to 2-nitro-1-(2,5-dimethoxyphenyl)ethane

10,5 g (50 mmol) 2,5-dimethoxy-beta-nitrostyrene was added during 5 minutes to a solution of 2,4 g  (63 mmol, 1,25 mol eq.) sodium borohydride in 50 ml water and 25 ml IPA1. The temperature rose from 20 to 50°C while the orange color faded to a slightly yellow. 2N HCl was then carefully2 added until pH 4 was reached followed by enough solid NaCl to cause the IPA to form a separate layer containing the product. Two volumes of water was added to the isolated IPA layer which caused 2-nitro-1-(2,5-dimethoxyphenyl)ethane to separate as a clear yellow oil and was isolated by extraction with 2x15 ml toluene. The organic phase dried over MgSO4 and the solvent removed under vacuum leaving the product as a clear yellow oil. Yield 9,7 g (46 mmol, 92%) 2-nitro-1-(2,5-dimethoxyphenyl)ethane.



Low-pressure hydrogenation of 2-nitro-1-(2,5-dimethoxyphenyl)ethane to 2C-H

The 2-nitro-1-(2,5-dimethoxyphenyl)ethane isolated above was added to a suspension of 2g 5%Pd/C in 50 ml EtOH (which had been treated with hydrogen under 4 bar pressure at 55°C for 10 minutes) followed by 15 ml GAA and 20 ml water. The pressure was kept at 5 bar for three hours and the temperature at 55°C. The reactor was opened and the catalyst removed by filtration then the EtOH was distilled away under reduced pressure. The remaining solution was extracted with 2x30 ml toluene, saturated with NaCl then the pH was raised to 14 and the amine isolated by extraction with 2x30 ml toluene. The organic phase was dried over MgSO4 and the solvent removed by distillation under reduced pressure leaving 2C-H as a slightly yellow oil. The amine was dissolved in EtOAc and acidified to pH 4 with 5N HCl/IPA and the hydrochloride isolated by filtration and dried to constant weight. Yield 7,8 g (36 mmol, 78%) 2C-H*HCl as white crystals.



[1] The reaction is so quick that the addition of NaOH to stablize the borohydride solution is not necessary.
[2] 1,25 Mol eq. borohydride was used to reduce the nitrostyrene. I believe less borohydride can be used since so much was left after the reaction was over as evidenced during acidification. About 1,05-1,1 mol eq. is probably enough.


Rhodium

  • Guest
Impressive!
« Reply #37 on: July 27, 2003, 10:27:00 PM »
If you continue to improve the synthesis of 2C-H at the same rate as you have been doing the past year, I believe that before the spring of 2005 the 2C-H will practically synthesize itself already when storing the reagents close to each other in an unventilated room  ;)

pHarmacist

  • Guest
Not only 2C-H
« Reply #38 on: July 28, 2003, 03:42:00 PM »
Not only 2C-H but even the fully active 2C-C since 2C-H.HCl is obtained and he menaged to get 2C-C from 2C-H.HCl according to another superb hall-of-fame BariumTM writeup...


Tricky

  • Guest
Please help with rxn, mentioned above.
« Reply #39 on: October 03, 2003, 03:30:00 PM »
Hi, bees!
SWIT got problem with wet reduction of 2,5DMNS.

Last night he did rxn, which was recommended by Barium:


10,5 g (50 mmol) 2,5-dimethoxy-beta-nitrostyrene was added during 5 minutes to a solution of 2,4 g  (63 mmol, 1,25 mol eq.) sodium borohydride in 50 ml water and 25 ml IPA. The temperature rose from 20 to 50°C while the orange color faded to a slightly yellow...
The mixture turn deep yellow, not slightly. It was stirred about 20 minutes, and then 2N HCl was added till pH=4, after this step SWIT had 2 layer: water-layer and deep orange oil, which collected on the bottom of beaker... Trying to separate this oil gave him a tar  :(  
Please, help.
What did he do wrong? May bee one need to stir solution more long or what???


Tricky

  • Guest
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

  • Guest
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

  • Guest
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

  • Guest
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

  • Guest
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

  • Guest
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

  • Guest
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

  • Guest
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

  • Guest
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

  • Guest
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

  • Guest
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

  • Guest
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

  • Guest
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

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

So nice!  8)

starlight

  • Guest
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

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

GC_MS

  • Guest
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

  • Guest
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

  • Guest
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

  • Guest
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


GC_MS

  • Guest
Yield
« Reply #60 on: October 21, 2003, 03:11:00 PM »
Yes, that's sweet work  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?


2 mol eq NaBH4? Yes.

Yield 56%? Not sure... Just take a look at the "impurity" DCM phase from B. There was quite alot of N-formyl-amphetamine. I don't think this should be simply neglected...  ;) .


starlight

  • Guest
great to have
« Reply #61 on: October 21, 2003, 04:26:00 PM »
GC_MS: great to have some objective measures of reaction performance under different conditions. Takes things further away from guesswork. Thanks for the effort that this entailed.

hest

  • Guest
Thank's
« Reply #62 on: October 21, 2003, 11:21:00 PM »
Nice work GCMS, I'll give thered with Pd/C and H2 or KOOCH a shot.

Bandil

  • Guest
Further tweaking
« Reply #63 on: October 23, 2003, 01:37:00 PM »
GC_MS>
When you say that the N-formyl-amphetamine should not be neglected, what precisely do you mean? Is it possible to salvage that somehow?

Also, where does the formylamphetamine come from? It it some sort of condensation reaction with amphetamine and formic acid? AFAIK formamide is formed at high temperatures from formic acid and ammonia. Could it be problem be that we are using IPA here, which allows the temperature to climb and thus allow the formation of the formylamphetamine?

Could it be an idea to tweak the reaction in the following way:
1: Use 2X borohydride(as you found out of course)
2: Perhaps use a bit less formic acid and keep the temperature in the range from 20-40 degrees, to avoid forming anything wrong?
3: Use potassionformate as they suggest in the original patent(we'll the use ammoniumformate, but AFAIK the potassium salt is a much better hydrogen donor). Maybe a less acidic envirnoment wont facilitate the formation of the formyl compound?

Think of how cool it could be to bring the yield of this reaction up on the side of LAH reductions. That would be close to revolutionary IMO  8)

Regards
Bandil


Rhodium

  • Guest
Alternative Explanation
« Reply #64 on: October 23, 2003, 03:22:00 PM »
N-[2-(1-phenylpropyl)]-ethylidenimine

Where the fuck does this come from?


I have seem Zn/formate catalyze retro-nitroaldol reactions before, giving the starting materials back, in this case benzaldehyde + nitroethane.

Formic acid most certainly is able to catalyze the reaction EtNO2 -> AcOH + NH2OH (see

Post 216169

(Rhodium: "R-CH2NO2 + Acid -> R-COOH + NH2OH", Chemistry Discourse)
)

The acetic acid is reduced to acetaldehyde, and then condenses with amphetamine. Result: N-[2-(1-phenylpropyl)]-ethylidenimine

However, there is something else that bothers me: amphetamine-benzaldehyde imine.

The benzaldehyde gotten in the retro-nitroaldol reaction also condenses with amphetamine. Result: amphetamine-benzaldehyde imine.

Bandil

  • Guest
Boosting yields
« Reply #65 on: October 31, 2003, 12:06:00 PM »
Since the major side reaction is the formation of the N-formyl amphetamine, how about just treating the whole lot like a pseudo-leuckart reaction?

After finished Zn reduction, most of the solvent could be stripped and then the residue mixed with some 15% hydrochloric acid and refluxed to two hours. Wont that hydrolyze the N-formyl compound?

Maybe thats the trick required to boost the yields further...

Regards
Bandil


eve

  • Guest
PTC
« Reply #66 on: October 31, 2003, 05:00:00 PM »
Sorry to bother, any other substitute PTC for the aliquat 336 ??

Bandil

  • Guest
No bother :-) But as you can read in the later
« Reply #67 on: November 01, 2003, 01:55:00 AM »
No bother  :)  But as you can read in the later in the thread, there is no need for a PTC at all...


Vitus_Verdegast

  • Guest
another PTC
« Reply #68 on: November 01, 2003, 05:51:00 PM »
SWIM has tried substituting the easily obtainable cetrimide (hexadecyltrimethylammonium bromide) for aliquat 336 in a water/DCM two-phase NaBH4 reduction of 2,5-dimethoxynitrostyrene, but only tar was obtained.

It might work for nitropropenes, though.


josef_k

  • Guest
Is there a possibility that you could use HCl...
« Reply #69 on: December 13, 2003, 02:11:00 AM »
Is there a possibility that you could use HCl instead of formic acid in the Zn reduction part of the method by bandil in this thread? Zn/HCl can reduce other nitro groups for example phenyl-2-nitropropanol. It would also avoid the formation of N-formylamphetamine.

GC_MS

  • Guest
Activated Zn
« Reply #70 on: December 17, 2003, 08:45:00 AM »
Although the Zn/HCOOH reduction involving inactivated Zn certainly works, I think it is more adventageous to use activated Zn.

Activated Zn is very reactive towards the added HCOOH. Adding HCOOH to Zn produces heat and lots of gas within a second. This is not the case for inactivated Zn. When you add HCOOH to inactivated Zn, it may be that no or little reaction is noted, resulting in adding more HCOOH. However, this will lead to a fountain making Trevi look like a pile of shit. The Zn starts reacting (after "in situ activation") with HCOOH "all the sudden" resulting in a reaction you don't have under control anymore.

It's a practical tip. If you doubt it, you are kindly invited to come to my lab for a cleaning session (interpretation of the latter depends on your gender).


Rhodium

  • Guest
Rh-catalyzed hydrogenation of nitroalkenes
« Reply #71 on: December 17, 2003, 11:22:00 PM »
Procedure for the Homogeneous Catalytic Hydrogenation of alpha,beta-Unsaturated Nitro Compounds using Triarylphosphine-Rhodium Complexes
Robert E. Harmon, Jack L. Parsons, and S. K. Gupta
Organic Preparations and Procedures 2(1), 25-27 (1970)

In recent years the homogeneous hydrogenation of carbon-carbon double bond in the presence of other reducible functional groups such as carboxylic acids, esters, aldehydes, ketones, nitriles, etc. has received increased attention1-5. The selective catalytic hydrogenation of an olefin in the presence of a nitro group is especially difficult. In this paper, we wish to describe a detailed procedure for the homogeneous hydrogenation of alpha,beta-unsaturated nitro compounds using tris(triphenylphosphine)chlororhodium(I) (1)1 and trichlorotris(4-biphenylyl-1-naphthylphenylphosphine)rhodium(III) (2)6. For instance, the hydrogenation of 3,4-methylenedioxy-ß-nitrostyrene (3) using the catalyst 1, afforded a 84% yield of 2-(3,4-methylenedioxyphenyl)-nitroethane (4). Similarly, the hydrogenation nitrostyrene (5) gave a 90% yield of 2-(2,5-dimethoxyphenyl)-2-nitropropane (6). Under identical reaction conditions (temperature 50°C, hydrogen gas pressure 80 psi, and reaction time 8 hr.), the catalyst 2 was found to be as effective as the well known Wilkinson's catalyst, 1.



Experimental

3,4-Methylenedioxy-ß-nitrostyrene (3) was prepared by the condensation of piperonal and nitromethane according to the procedure of Lange and Hambourger7. 2,5-Dimethoxy-ß-methyl-ß-nitrostyrene (5) is commercially available. Tris(triphenylphosphine)chlororhodium(I) was prepared by the reaction of an excess of triphenylphosphine with rhodium trichloride trihydrate according the procedure of Wilkinson and co-workers3. Trichlorotris(4-biphenylyl-1-naphthylphenylphosphine)rhodium(III) was prepared by the reaction of 4-biphenylyl-1-naphthylphenylphosphine with rhodium trichloride trihydrate2.

All solvents were deoxygenated by refluxing under a stream of argon for 3 hours, followed by storage under argon. Melting points were taken on a Thomas-Hoover melting point apparatus and are corrected. The hydrogenations were performed in a medium pressure hydrogenation apparatus.

The Hydrogenation of 3,4-methylenedioxy-ß-nitrostyrene (3)

The compound 3 (2.5 g, 13.0 mmol) and tris(triphenylphosphine)chlororhodium(I) (1) (0.40 g, 0.44 mmol) were dissolved in 300 ml of benzene under an argon atmosphere. The solution was transferred to the medium pressure reaction vessel and flushed with hydrogen gas 5 times. The reaction mixture was stirred for 9 hours at 60°C under a hydrogen gas pressure of 60 psi. After completion, the benzene was evaporated under reduced pressure. The oily residue was mixed with 50 ml of ethyl ether and filtered to remove the insoluble catalyst. The filtrate was evaporated to dryness. The residue was redissolved in ether, filtered, and the ether removed to give 2.1 g (84%) of 2-(3,4-methylenedioxyphenyl)-nitroethane (4), mp 53-54°C.   

The Hydrogenation of 2,5-Dimethoxy-ß-methyl-ß-nitrostyrene (5)

The compound (3.0 g, 13.4 mmol) and trichlorotris (4-biphenylyl-1-naphthylphenylphosphine)rhodium (III) (0.40 g, 0.29 mmol) were dissolved in 300 ml of benzene-ethanol (1:1) under an argon atmosphere. The resulting clear red solution was transferred to the reaction vessel and after flushing 5 times with hydrogen gas, stirred for 12 hours at 60°C under a hydrogen gas pressure of 100 psi. Then the solvent was removed under reduced pressure and the remaining oil vacuum distilled to give 2.7 g (90%) of 2-(2,5-dimethoxyphenyl)-2-methyl-nitroethane, bp 135-140°C (0.1 mm). 

References
[1] J. A. Osborn, F. H. Jardine, J. F. Young, and G. Wilkinson, J. Chem. Soc., A, 1711 (1966)
[2] A. J. Birch and K. A. M. Walder, J. Chem. Soc., C, 1894 (1966)
[3] C. Djerassi, J. Gutzwiller, J. Amer. Chem. Soc., 88, 4537 (1966)
[4] F. H. Jardine, J. A Osborn, and G. Wilkinson, J. Chem. Soc. A, 1574 (1967)
[5] A. S. Hussey and Y. Takeuchi, J. Amer. Chem. Soc., 21, 672 (1969)
[6] R. E. Harmon, J. L. Parsons, and S. K. Gupta, Organic Preparations and Procedures, this issue
[7] N. Lange and N. Hambourger, J. Amer. Chem. Soc., 53, 3865 (1931)


josef_k

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I tried Bandils method, but I used 2 eq of...
« Reply #72 on: February 03, 2004, 04:36:00 PM »
I tried Bandils method, but I used 2 eq of NaBH4 instead. Otherwise to the letter. But I only got 1g amphetamine sulphate.

Then I instead tried GC_MS method B, but scaled up to use 80g phenyl-2-nitropropene, and I used only 6.66 eq of zinc. After I boiled down the solution after the zinc reduction I added some 20% HCl and refluxed for 2 hours to convert the N-formylamphetamine to amphetamine. But in the end I only got 9g amphetamine sulphate.

I can't understand why I get so lousy yields. In the last reaction my mag stirrer couldn't really keep up, so there was some unreacted zinc. But that wasn't an issue in the first reaction. Could it be some impurity in the IPA? Perhaps I used to little 10% HCl in the A/B? The NaBH4 is of general purpose grade from Fischer, but they usually make quality chemicals, so that shouldn't be the problem.

Anyone have any hints?

Bandil

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I would like to try that particular reaction...
« Reply #73 on: February 04, 2004, 08:31:00 AM »
I would like to try that particular reaction with potassium formate instead of formic acid, as they seem to get higher yields in the original patent while using KHCOO. The reaction also runs less hot AFAIK, which might give this reaction an advantage.

But great initiative on trying to reflux in hydrochloric acid...

I'll post once i have tried the KCOOH scheme to see how that works in i comparison to!

Regards
Bandil


Rhodium

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Not novel, but a classic reference
« Reply #74 on: March 03, 2004, 12:13:00 AM »
Silica Gel-Assisted Reduction of Nitrostyrenes to 2-Aryl-1-Nitroalkanes with Sodium Borohydride
Achintya K. Sinhababu and Ronald T. Borchardt

Tetrahedron Letters 24(3), 227-230 (1983)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/ns.nabh4-silicagel.pdf)

Summary
Reduction of a variety of nitrostyrenes with sodium borohydride in the presence of silica gel in a mixture of chloroform and 2-propanol furnished the corresponding nitroalkanes free of dimers in near quantitative yields.


Rhodium

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2,5-DMNS --Ru/H2--> 2C-H (95%)
« Reply #75 on: June 02, 2004, 01:22:00 AM »
Preparation of 2,5-dimethoxyphenylethylamine by liquid-liquid catalyst hydrogenation of 2-(2,5-dimethoxyphenyl)nitroethene
Shi, Ying; Du, Xi; Chen, Hua; Li, Xian-jun; Hu, Jia-yuan.
Faculty of Chemistry,  Sichuan University,  Chengdu,  Peop. Rep. China.
   
Shiyou Huagong 32(12), 1051-1054 (2003)
CODEN: SHHUE8  ISSN: 1000-8144.  Journal  written in Chinese. CAN 140:289167 AN 2004:38137

Abstract
2-Nitro-(2,5-Dimethoxyphenyl)ethene (I) and its hydrogenation product are widely used in fine chem. synthesis.  Catalytic performances of RuCl3 - TPPTS (P(C6H4SO3Na)3) as catalyst precursor for selective hydrogenation of both C=C and -NO2 groups in I had been studied in biphasic catalytic system (aq./org. phase).  After a long reaction time of about 20 h, conversion inctreased substantially and the selectivity for hydrogenation of both C=C and -NO2 groups increased.  Reaction conditions were: c(Ru) = 3 mmol/L, TPPTS/Ru mole ratio = 6, pH2 = 4.0 MPa and 90°C. Hydrogenation of arom. ring was not found (or did not occur).  Addn. of a surfactant (cetyltrimethylammonium bromide, CTAB) to the system obviously decreased the hydrogenation activity as welt as the selectivity for hydrogenation of both C=C and -NO2 groups although, in general, presence of the surfactant (CTAB) was known to increase hydrogenation activity.  Steric hindrance of the surfactant micells formed might possibly decrease the soly. of 2-(2,5-dimethoxyphenyl)nitroethene in biphasic catalytic system.  Under the best reaction conditions, the conversion of substrate reached 95.0%.  It was easy to sep. the hydrogenation product from the catalyst after the reaction.