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All 34 posts Subject: A great CTH method Please login to post Down

Barium
(Hive Bee)
11-22-02 16:00
No 382254
      A great CTH method
(Rated as: excellent)

Ammonium formate/Pd-C is the most commonly used CTH-system I´ve seen. It has been used to reduce -NO₂ --> NH₂, =NOH --> NH₂ to name a few types of reductions. In the literature the reduction of aromatic nitro groups are far more common than reduction of alphatic nitro groups. This bad for us, since we have more often a far greater interest in reducing aliphatic nitro groups. The ammoium formate/Pd-C system is awesome for aromatics but can be very troublesome for aliphatics.

I´ve over the years had some success with the ammonium formate/Pd-C system for alipahtic nitro groups, in some cases with great yields. But far more often terrible yields. This is even though I´ve used 10 mols formate/mol nitro. mad So cursing like mad, I´ve usually ended up using excess Red-Al instead of dirt cheap formate CTH. frown

In the literature it´s stated that the different formate salts behave very different as hydrogen donors. Formic acid is usually the poorest donor, sodium formate is better , then ammonium formate (and trialkylammonium formates) and finally the best donor is potassium formate. In
Patent US4792625 potassium formate is used in a CTH procees for various aromatic nitro compounds. I tried this method to make some 2C-H in Post 326004 (Barium: "Better yields", Novel Discourse) with decent yields (64%). For some reason I completely forgot all about this system until two days ago. This method was now tried with a few nitroalkanes to see how useful it was as a overall CTH method for aliphatic nitro groups.

General method

50 mmol nitroalkane
250 mmol potassium formate
750 mmol water
25-50 ml IPA (depending on how much is needed to get a nice solution)
10%w/w 5%Pd/C (catalyst to substrate)

Add the catalyst to the reaction flask and and wet it with the water. Then add the nitroalkane dissolved in IPA and finally the formate. With good stirring, heat the reaction mixture to about 70°C on a water bath for 1-3 hours. The reaction is over when gas evolution ceases.

Here comes a nice twist.
when the reaction is over one can carefully acidify the solution to pH 2-3, filter off the catalyst and perform the workup as usual.
Or, filter off the catalyst/KHCO₃ and wash it with IPA. Dry the IPA solution with MgSO₄ and distill off the IPA to get the crude amine. Save the filter cake, because when the next batch of the same amine is to be made just dissolve the nitroalkane in IPA, add the filter cake and finally 250 mmol formic acid. Voila, potassium formate regenerated.
Do I need to mention that formic acid is dirt cheap?!

2-Nitro-1-(2,4,5-trimethoxyphenyl)-propane --> TMA-2*HCl 89%
2-Nitro-1-(3,4-ethylenedioxyphenyl)-propane --> EDA*HCl 84%
2-Nitro-1-(2-fluorophenyl)-propane --> 2-FA*HCl 85%
2-Nitro-1-(2,4,5-trimethoxyphenyl)-ethane --> 2,4,5-TMPEA*HCl 85%
2-Nitro-1-(2,4-dimethoxyphenyl)-ethane --> 2,4-DMPEA*HCl 91%
2-Nitro-1-(2,5-dimethoxyphenyl)-ethane --> 2C-H*HCl 89%

I will try this potassium formate CTH system for reduction of imines and oximes.
Catalytic hydrogenation freak

Rhodium
(Chief Bee)
11-22-02 16:09
No 382255
User Picture       Barium - our CTH expert!

Good, better, great!

Have you tried using this CTH system directly on any nitrostyrenes, eliminating any need for reducing the alkene to the alkane separately, using sodium borohydride?

Also, how many times do you usually recycle your Pd/C, before it loses activity? Is it "safe" to store the catalyst together with the potassium salts for extended periods - it won't decompose or anything?

Barium
(Hive Bee)
11-22-02 16:20
No 382259
      Thank you chief

No I haven´t tried it directly on nitrostyrenes, but I will now when you´ve mentioned it. The filtercake can be stored dampened with water. Add enough water to get a wet slurry and cover it with aluminum foil. The catalyst should not be affected by the potassium salts at all.
The catalyst can be reused at least five times.

Degussa (catalyst manufacturer) claim that a small addition of Fe salt makes Pt and Pd catalysts more efficient for -NO2 reductions. This will also be investigated.

Catalytic hydrogenation freak

L42L
(Stranger)
11-25-02 22:23
No 383289
      barium you f-in rock!

It's like every time I look you got some more cool stuff. Saving my Pd/C for the day you bring us a DMT synth. Can't wait to see what happins with the styrene, best of luck!
thanks
lurk

Barium
(Hive Bee)
11-27-02 14:36
No 383891
      Tested

10 g 2,4,5-Trimethoxy-beta-methyl-beta-nitrostyrene (39.5 mmol)
HCOOK (240 mmol)
HOAc (240 mmol)
1 g 5%Pd/C
75 ml EtOH
40 ml water

Everything was mixed except the acetic acid. Gas evolution started immediately, unlike when IPA is used. The reaction mixture was placed in a water bath and heated to 55°C with good stirring. Every now and then during 90 minutes 1 ml acetic acid was added to prevent the bicarbonate to precipitate. If the acetic acid was added in this manner the pH never ever fell below 8, since the potassium acetate is a basic salt. The workup was identical to the previous reaction. The acid extract was saved and isolated to give the ketoxime in a good yield.

The really interesting part was what was recovered from the alkaline extractions. When the solvent was removed no oily amine remained at all despite something showing amine-like behaviour, when the water phase was made alkaline, fell out of solution. Instead it was a white waxy crystalline material. Totally unlike the ketoxime, amine, nitropropene or nitropropane. It was even only very slightly soluble in EtOAc. The suspension in EtOAc was very alkaline so I believe it can actually be N-OH-TMA-2. I added dry HCl/IPA until pH 5 was reached and the waxy solid transformed into a fine crystalline powder.

Yield 3.8 g of 2-(N-hydroxyamino)-1-(2,4,5-trimethoxyphenyl)-propane*HCl (N-OH-TMA-2)????? shocked
Catalytic hydrogenation freak

Rhodium
(Chief Bee)
11-27-02 14:41
No 383892
User Picture       Interesting. Be sure to keep us updated on the ...

Interesting. Be sure to keep us updated on the analysis of this. An easy route to the N-OH derivatives of phenethylamines opens up a parallell universe of interesting "twins" to popular amines, which are not covered by any laws in most countries.

Barium
(Hive Bee)
11-28-02 16:41
No 384333
      Dare I say quantitative yield
(Rated as: excellent)

10 g 2-Nitro-1-(2,4,5-trimethoxyphenyl)-propane (39,2 mmol)
20,5 g HCOOK (roughly 240 mmol) dissolved in 50 ml water
2 g 5% Pd/C (20% w/w)
100 ml EtOH (feel free to substitute this for IPA or MeOH)
14,5 ml HOAc (240 mmol)

The catalyst was added to a 500 ml E-flask equipped with a magnetic stirbar and wetted with 5 ml water. The EtOH was then added followed by the nitropropane and the potassium formate solution. The reaction mixture was stirred and heated to 55°C on a waterbath. When the preciptitated bicarbonate made the mixture difficult to stir the acetic acid was added one milliliter at a time until the salt went into solution again. This procedure was done two times during one hour, at which time the reaction was over.

The catalyst was removed by filtration through celite and saved. The filtrate was colorless with a pH of 12,7. Acetic acid was added until pH 7 was reached and the EtOH removed by distillation in a rotovap (save this because it can be used again as it is). The aqueous solution was made alkaline (pH 13) with NaOH, saturated with NaCl and extracted with 2x50 ml toluene. The combined toluene extractions was dried by azeotropical distillation in the rotovap and the remaining toluene was also distilled away. This left a oil with just a hint of yellow color. 100 ml EtOAc was added to the oil and dry HCl/IPA was added until pH 6,5 was reached. The crystals, which started to form immediately when the HCl was added, was isolated and dried to constant weight.

Yield: 10,1 g (98,5%) TMA-2*HCl as absolutely white crystals. *sniffle* crazy
Catalytic hydrogenation freak

Triton
(Newbee)
11-29-02 10:43
No 384557
      Sorry if this is off-topic, but...

How does one separate the catalyst from celite?

Barium
(Hive Bee)
11-29-02 14:38
No 384589
      Don´t worry

There is no need to separate the catalyst from the celite at all. Just dump in the filtercake into the reaction vessel for the next reduction. The celite doesn´t disturb anything. When that reaction is over you do not need to add any celite since it is already present.
Catalytic hydrogenation freak

Ritter
(Master Whacker)
12-06-02 00:13
No 386641
      alkene reduction?

Hi Barium,

Wow, you sure are doing some fine work here these days, thank you for sharing!!! Congrats on mastering the CTH of nitroalkanes! I do have a somewhat related question- you have posted numerous writeups concerning the reduction of the nitroalkane to the amine however you have not said much about the reduction of the nitroalkene to the desired nitroalkane lately. Have you done any work to improve the NaBH4 reduction of the nitroalkene such as working out a new solvent system or are you still using the same ethyl acetate solvent system described in your very first post on this topic? In passing, you have also mentioned toluene worked well for the alkene reduction, I'm just wondering what solvent and reaction parameters you prefer after so much experimentation?

Barium
(Hive Bee)
12-06-02 17:41
No 386900
      Hi Ritter

For most phenylnitropropenes there is no need to use the EtOAc/EtOH system. Instead, to a suspension of the nitropropene in MeOH, EtOH or IPA solid NaBH₄ is added portionwise until the yellow color is completly gone. Then adding twice the volume water and destroying the excess borohydride with acetic acid, distilling off the alcohol and extracting the nitropropane with some NP solvent gives yields in the range 60-95%, depending on the substrate.

Phenylnitroethenes on the other hand needs the toluene/EtOH or EtOAc/EtOH system to give good yields.

I will post a write up on this topic in a little while.
Catalytic hydrogenation freak

Megatherium
(Stranger)
12-15-02 20:53
No 389730
      Are there problems to be forseen when one applies ...

Are there problems to be forseen when one applies this reaction on thienyl-2-nitropropanes & furoyl-2-nitropropanes? Isn't the furoyl ring going to be reduced (since the resonance energy of furane is considerably lower than the one of thiophene and benzene). And with thiophene, is there a risk of catalyst poisioning?

Rhodium
(Chief Bee)
03-12-04 21:29
No 494690
User Picture       One-Pot Nitroalkene -> Amine using CTH?
(Rated as: excellent)

The following two articles describe 1) The reduction of nitrostyrenes to oximes and 2) the reduction of oximes to amines, respectively. Both are CTH reactions using Pd/C and Ammonium Formate, and both use alcoholic solvent mixtures. Shouldn't it then be possible to reduce nitrostyrenes to amines in one-pot, using long reaction times and a stronger hydrogen donor like potassium formate?

One trial like this was posteded in Post 383891 (Barium: "Tested", Novel Discourse) but there was no closure regarding the product identity, and the reaction time was very short - maybe it could benefit from being run overnight or so?

Oximes from Conjugated Nitroalkenes Using Pd/C-Ammonium Formate CTH
G. W. Kabalka, R. D. Pace, and P. P. Wadgaonkar
Synth. Commun. 20(16), 2453-2458 (1990) (https://www.rhodium.ws/chemistry/nitroalkene2oxime.cth.html)

Abstract
Conjugated nitroalkenes are readily reduced to the corresponding oximes in good yields using ammonium formate in the presence of palladium. The reactions occur rapidly at room temperature in a solvent system of methanol and tetrahydrofuran.

_{This article has been mentioned earlier in the following post: Post 228726 (Cyrax: "Re: Synthesis of amphetamines", Methods Discourse)}
____ ___ __ _

Palladium-catalysed Transfer Hydrogenation of Azobenzenes and Oximes using Ammonium Formate
G. K. Jnaneshwara, A. Sudalai and V. H. Deshpande
J. Chem. Research (S), 160-161 (1998) (https://www.rhodium.ws/pdf/cth.oximes.formate.pdf)

Abstract
The reductive cleavage of azobenzenes, including the reduction of oximes to their corresponding amines, has been achieved with Pd⁰ using ammonium formate as hydrogen source.

_{This article has been mentioned earlier in the following post: Post 368992 (Rhodium: "CTH Oxime Reduction", Methods Discourse)}

^{The Hive - Clandestine Chemists Without Borders}

armageddon
(Stranger)
03-23-04 02:58
No 496762
      Pd/C hydrogenation of imines?

Rhodium, the one-pot nitroalkene->aminoalkane you suggest here could indeed bee a nice shortcut, as it avoids the rather expensive NaBH₄ used for double-bond reduction. SWIM recently tried something similar, but with shorter reaction times (like 45min) and ammonium formate as hydrogen donor (6-7x molar excess), and the results were not very promising, because something like 1% yield laugh (based on substrate phenyl-2-nitropropene) was obtained. But, as you say, a stronger hydrogen donor like potassium formate and longer reaction times might do the trick in this case. Or perhaps the efficiency of the procedure could be increased by slowly adding formic acid to rxn mixture via dripping funnel. I think this would regenerate in situ the used KCOOH, or would the acid have no time, as it is decomposed directly upon coming in contact with the catalyst? I wouldn't think so, and even if that was the case, HCOOH is a weak hydrogen donor in CTHs AFAIK, like in Zn/HCOOH reactions, so that wouldn't matter at all.
But to achieve simultaneous reduction of the double bond and nitro group, ideal rxn conditions are difficult to realize because alipathic C=C bonds are best reduced at relatively mild temperatures in a moderately polar solvent, whereas NO₂->NH₂ proceeds best at elevated temperatures (100-150°C I think) and anhydrous conditions, with the aid of GAA as cosolvent(according to degussa, no.1 catalyst manufacturer). I think the GAA would somewhat interfer with KCOOH, right? SWIM will still give it a try, using alcohol as solvent, with perhaps a bit of formic, and potassium formate. Rxn temp. will bee maintained at +-70°C, time perhaps 5-6 hours: what do you think? And since SWIM has no KCOOH, he could get it by reacting anhydrous KOH with 99% HCOOH in iPrOH (perhaps with silicagel) under cooling, right?

Barium, I am very interested: have you already tested your potassium formate CTH on imines? If this would work, I bet it would be possible to get methamphetamine by reducing phenylacetone with Pd/C with in situ methylamine generation from nitromethane, similar to Al/Hg nitromethane reductions. As far as I understand, Al/Hg is capable of reducing both ketones and nitroalkanes, the former reacting with amines to give imine intermediates which are protonated, the latter being straight hydrogenated. And Pd/C is also capable of reducing ketones to amines with an amino group donor like ammonium acetate/formate, besides of being of great use for nitro->amine reductions (phenyl-2-nitropropanes or nitromethane, giving the corresponding amphetamines or methylamine)..
Perhaps a good route for bees without access to methylamine and much better than having to deal with hg salts! The great disadvantage of al/hg nitromethane reactions.. ..together with painful workups!! frown
The only question left would be if palladium/charcoal is capable of reducing imines. If this works, one could react p2p with amm.formate, a pd/c catalyst and slow addition of nitromethane, or perhaps P2P and CH₃NO₂ premixed and calculated amounts added to Pd/C and LOTS of NH₄COOH... Work to bee done! wink

Thanks, A

Barium
(Heavyweight Chempion(eer))
03-23-04 12:44
No 496830
      So far I have not seen a CTH-system capable of

So far I have not seen a CTH-system capable of selectively reduce the C=C bond in a phenylnitroalkene. To succeed with this a catalyst with high affinity for the C=C bond and a very very low, or no affinity at all for the nitro group must be used. A catalyst with such properties are to be found among the homogenous family. With every hydogen donor I have seen so far, combined with Pd, the nitro group is reduced to a hydroxylamine. This gives a hydroxylenamine since the double bond is still intact and the hydroxylenamine tautomerizes immediately to the oxime.

Aliphatic oximes are kind of tricky to reduce further. Aromatic oximes on the other hand are really easy to reduce. In the articles above all the oximes are aromatic. Not even Kabalka have presented a CTH system which reduces aliphatic oximes.

armageddon
(Stranger)
03-23-04 14:27
No 496838
      hydroxylenamines

First of all, thx for your quick response Barium!

So to speak, Pd/C is NOT capable of simultaneous reduction of double bonds AND alipathic nitro groups, since it prefers attacking the NO₂ group, leaving something like C₆H₅CH=C(CH₃)NHOH, which in turn tautomerizes to phenylacetone oxime before the catalyst has time to attack the f***ing double bond.

But still I think pd might bee useful in that case, I think of Post 335851 (Sunlight: "MDA and MDMA from CTH reductive amination", Novel Discourse) where sunlight successfully reduced ketones with an amino group donor, formic acid and pd/c (methink), and all those old writeups about al/hg oxime reductions https://www.rhodium.ws/chemistry/alhg.oxime.html where the only difference to normal ketone al/hg's is the acidic, aequous environment. To repeat it: Al/Hg and Pd/C both are capable of reducing ketones and nitro groups to their amino derivatives, and I don't understand why pd/c should let oximes unaffected whereas al/hg would reduce them!? It would bee just too nice and easy..
Oh, not to forget: zinc and formic (or was it HCl) reduce nitropropenes to P2Ps and amphetamines (minor), and I think ("nose chromatography", SWIMs only method of analysis crazy ) that pd/c does something similar to nitrostyrenes, as SWIMs Xperiments showed amphetamine was produced in minor amounts (he got ~150mg sulfate), accompanied with strong p2p smell. Perhaps Pd/C acts similar to Zn/H+? But it also works on ketones, so why should styrenes give something useless (styrene->ketone->amine)?

(perhaps Kabalka didn't try to reduce oximes, if he did: was anything ever published? something where he states oximes cannot be reduced by pd/c and hydrogen donors? The fact that one researcher (although being VERY competent) didn't confirm the possibility of such a reaction is NO PROOF of its impossibility in general, I think smile Show me a published statement like "according to our experiment, its impossible" and I will believe it, but if everyone just thought everything was impossible because his favourite researcher didn't work on the subject, noone would EVER discover anything new, right? wink )

And still I'm left with an important question: would Pd/C work on amphetamine methylimine (obtained by reacting p2p w/methylamine, in situ or in an extra reaction?) and produce methylamphetamine by hydrogenating the =N to NH ? Remember Pd/C does reduce nitroalkanes to their amines, hence also nitromethane->methylamine. SWIM thinks this could turn out to become a easy onepot meth synth without mercury salts or high pressure involved... perhaps it would bee just TOO easy that way and is therefore not possible crazy ...

Any comments are welcome!!

Greetz A

hest
(Hive Adickt)
03-23-04 15:55
No 496845
      Pd/C and nitralkenes

There have been some effort to try to make this work here at the hive, but with no luck at all.
Iff you try and work up the product by A/B you end up with the oxime, with smel's aminelike and give some flufy material with ether HCL but it's not the amphetamine(phenetylamine). The problem is the conjugation beetwen the dob.bond and the nitrgroup. Only solution is to red. the dob.bond with NaBH4 and then CTH of the nitrogroup.

As you say, this way would bee to easye *lol*.

josef_k
(Hive Bee)
03-23-04 19:16
No 496867
      Re: There have been some effort to try to make

There have been some effort to try to make this work here at the hive, but with no luck at all.

What about this then: https://www.rhodium.ws/chemistry/nitropropene.cth.txt
Very large amount of catalyst though.

armageddon
(Stranger)
03-23-04 19:25
No 496868
      noone knows of imine reductions?

Hmm, I just read a very interesting analysis done by GC_MS (great work!!! THX a lot!) on Zn/HCOOH reductions of nitropropanes obtained by NaBH₄ reduction of nitrostyrenes (UTFSE for posts by GC_MS containing "reanalysis nabh4 zn/hcooh"), some P2P impurities were present and he too assumed that unreacted nitropropene (insufficient NaBH₄ was used) was reduced to phenyl-aminopropene, being tautomerized and hydrolized to P2P. He also concluded this had to be minimized because of P2P amphetamine condensation by-products...
Yet another reason why nitropropene->aminopropane reductions won't work with pd/c. Even if some of the nitropropene got reduced to nitropropane, there would be enough aminopropene formed to give mainly ketone-amine condensation products in the end, right? But on the other hand, there is a procedure by Sunlight (see my above post) that uses Pd/C, ammonium formate at room temp. and long, long rxn times (16-48h) to go from the ketone to the amine (using MDP2P as substrate, yielding MDA), wierd!

Anyway, the easiest, highest yielding and least dangerous (LAH,THF,hydrogen/pressure,HgCl₂-not needed anymore laugh !) method to reduce nitrostyrenes to their amphetamines is borohydride reduction, followed by hydrogenation with either Zn/formic acid or Pd/C and some formic acid salt (or again NaBH₄) - yields are on the high side: 60-90% depending on the nitroalkene substrate are achieved in each reduction step, often there is even no need to work up the intermediate product - and everything can be applied to almost any known nitrostyrene! Already easy enough, dare I say hest! smile And it gets better: borohydride is being researched as future fuel replacement in fuel cell cars, that means availability will surely become better within the next years wink ! poor pigs, might I say! cool

Still noone who has tried to reduce imines with pd/c? Seems as if SWIM will have to figure it out by himself.. smile

Greetz A

Barium
(Heavyweight Chempion(eer))
03-23-04 20:17
No 496875
      Imines

Sunlights work to reductively aminate MDP-2-P with in situ generated ammonia from ammonium formate shows that notoriously sensitive imines are reduced in good yields with Pd. Pd can of course also be used with molecular hydrogen under pressure. A way to improve yields in CTH reductive aminations and alkylations would possibly be to swap Pd for Pt. Perhaps doped noble metal catalysts or doped Raney catalysts would be even better.

armageddon
(Stranger)
03-24-04 00:27
No 496926
      methylimine to methylamph

Thank you Barium! I have read sunlights (excellent) CTH thread several times, but still I have overread important facts, as you showed me shocked ..

And as the rxn proceeds at room temp. it wouldn't be a great deal to try it with careful addition of some nitromethane (being reduced to methylamine) instead of ammonia, perhaps with external cooling (nitromethane loves being reduced and evolves considerable heat) to see if methylamphetamine would bee the result. Or if it doesn't work this way, one could at least try it with methylamine (from MeNH₂*HCl and NaOH) premixed with phenylacetone, should work as far as I understand (tell me if I'm wrong here). Still the advantage would be to avoid nasty, poisonous Al-(whatever)-sludges frown .

Josef_k: sorry to say, but the procedure is bullshit (sorry dreamer), SWIM tried the procedure several times, also with exact amounts of lab-grade high purity chemicals and bright-yellow, sparkling nitropropene as substrate, and got next to nothing (~1% of theory), so you could as well try it with Zn/HCl and yield up with roughly the same amount - next to NOTHING! mad When SWIM reduced first with borohydride, followed by Pd/C-ammoniumformate CTH, yields climbed way up (still not same as, let's say, Bandil, Barium or GC_MS to name a few, but I think that SWIMs skilled enough so he should have got at least SOMEthing IF this procedure would work AT ALL or even only half as good as described by dreamer.

Would just bee too easy, I keep saying! crazy

Greetz A

--oh, laughing is good for your health: http://195.92.224.73/j20/content/mainhost.asp laugh

armageddon
(Newbee)
03-24-04 17:44
No 497062
      ketone + amine + borohydride - no catalyst at all?

Well, I just stumbled over following thread: Post 461926 (cublium: "NaBH4 is just amazing.", Newbee Forum)
Apparently imines are protonated with plain borohydride - so there is no need for any catalyst at all if you have ketone and methylamine?

Just throw ketone and amine together with some solvent, add borohydride under cooling, let stir for a while - et voilà, methylated amphetamine? WAY too easy I think! shocked That means every fool can make meth once he gets his hands on some NaBH₄!! (well almost wink )

So the "only" use left for SWIMs Pd/C would bee formate CTHs where non-methylated amines are desired. Hm.

Oh, by the way: what about ring-substituted, methylated amphetamines, "psychedelic methamphetamine analogues"? Are they psychoactive at all? Does PIHKAL include some? I don't think so, but I'm just guessing..

Rhodium
(Chief Bee)
03-24-04 20:35
No 497080
User Picture       Several dozens of methods are available...

Apparently imines are protonated with plain borohydride - so there is no need for any catalyst at all if you have ketone and methylamine?

Imines aren't protonated by borohydride, they are reduced. NaBH₄ is a reducing agent in its own right, so yes, it can also be used for reductive amination (preferably under water-free conditions, but gives moderate yields without).

^{The Hive - Clandestine Chemists Without Borders}

Barium
(Heavyweight Chempion(eer))
03-25-04 01:58
No 497141
      Ahem! Someone really need to UTFSE a bit. :-P

Ahem! Someone really needs to UTFSE a bit. tongue

armageddon
(Newbee)
03-25-04 20:11
No 497330
      euhmm... yes.

I'm ashamed, all those things indeed are there, I was just too lazy to UTFSE. I was just searching in the wrong direction.. ;)

armageddon
(Newbee)
03-26-04 16:09
No 497521
      back to the subject ;^)

Ok I think this thread got a bit sidetracked because I just wasn't able to shut up (as usual, but where else can you talk to someone about OUR interests?) So I believe its time to post something reasonable.

nitrostyrene->amine with Pd/C/amm formate CTH pseudo-one-pot style, this is how SWIA does it:

100mmol (16,3 gram) nitrostyrene (P2NP, HIGH purity)
150mmol (5,7 gr) borohydride (NaBH₄)
115 ml IPA
45 ml H₂O
some xx ml 60% acetic acid (didn't measure)
~2 ml GAA
500mmol (~31g) NH₄COOH
4,2 grams Pd/C 10% (bought, not homemade)

a) Borohydride reduction First SWIA dissolved 5,7g borohydride in 115ml IPA and 45ml water with good stirring. After it had dissolved he added his nitropropene in small portions so that rxn didn't become too violent (gas/heat evolution made this necessary). The addition took 20 minutes, every portion nitropropene caused a color change to yellow which faded to almost white very quickly. After the addition everything was stirred for another 30 minutes, then ~5ml water was added, followed by small amounts of 60% AcOH (to destroy excess borohydride) until gas evolution had ceased completely and the mixture had become almost colorless, then a last 2ml was added. The rxn mixture was decanted from some white, sticky borate goo at the bottom, saturated with NaCl and the resulting upper alcohol layer (slightly yellowish) was separated and washed again with brine.

b) Pd/C CTH Next, SWIA weighed out 4,2 grams of 10% Pd/C (one half of it was already used and reactivated, and the other half was fresh from the bottle), put them in a 250ml RBF (bit too small crazy ), added the IPA/nitropropane solution gotten from the borohydride reduction and introduced ~31 grams ammonium formate. This was stirred violently for 5 minutes to dissolve as much formate as possible and then a reflux condenser was attached and temp. was slowly raised to 65°C on a water bath. When this temp was reached 45 minutes had passed already, but the rxn had just started to evolve lots of CO₂ and apparently hydrogenation had just begun, so SWIA decided to let it run at least another 45 mins. In the end, he waited until gas evolution had nearly ceased (to be sure hydrogenation was complete), took 3 hours in total (from additon of formate until heat was removed and the condenser was disconnected). After 1,5hrs 2ml GAA were added to prevent bicarbonate clogging in the condenser. After rxn had cooled down to RT it was filtered (very nice, clear, bright yellow soln, smelled alot ammonia) and saturated with NaCl. The resulting alcohol layer was separated, aeq. phase extracted once with 50ml toluene and the extraction and alc. layer combined, washed with sat. NaOH and then brine in order to remove ammonia (smelled still like household cleaner smile ). Then, SHOCK! SWIAs only drying agent at hand is CaCl₂, not suited for drying amines, nor alcohols. Well, SWIA thought, perhaps the water will bee removed azeotropically when I distill away some solvent (thinking of dean-stark traps), so he cooled, added solid NaCl until soln. became clear, and distilled almost all solvent away and was left with a dark yellow, oily residue with a strong amine smell.. (perhaps vac. dist. would've been better here, before applying heat the color was WAY brighter, obvioulsy something got decomposed; but SWIA has only ONE tap, no pump, hence he can only distill, reflux OR vac.filter, none of these at the same time mad )
The residue was dissolved in 4x its volume IPA, H₂SO₄ 98% was added in 0,1ml aliquots, everytime the solution got slurried with crystals SWIA added a few ml's Et2O and filtered. The crystals were washed with more Et2O (2x) until they had a shiny white color. Yield: 5,4 grams (phenyl-2-aminopropane)₂*H₂SO₄, 29% of theory (based on starting material phenyl-2-nitropropene) But SWIA suspects yields would've been higher if he had used REALLY anhydrous solvents for crystallization... crazy And he's very sure that without his attempt to dry a solution by azeotrope distillation, the salt obtained would've been very pure (without washing), as the crude amine soln. had a very pale yellow color (really nice appearance for freebase!)

But more important: it works simple, fast and WITHOUT having to isolate the intermediate nitropropane!
Next time SWIA will try it with KCOOH to see if rxn time can perhaps be shortened..

greetz A

Oh I forgot: in SWIAs opinion there was no need to do an A/B because normally, after ABing/extracting his non-polar has the same color like the post-rxn solution he got this time, so he assumed that there were very few side products (besides they don't really interfer when making the sulfate - opposed to water wink ). And furthermore the very strong ammonia smell convinced SWIA that the mixtr. was already basic enough to release its goodies upon Xtraction.. with KCOOH that's perhaps not the case - or is it perhaps decomposed to KOH? Then there would bee no need to basify, too, right?
S. Ram & R.E. Ehrenkaufer report the use of a somewhat similar procedure: "..the catalyst was removed by filtration through a celite pad and washed with dry methanol (10ml). The filtrate was evaporated either under reduced or at normal pressure. The resulting residue was triturated with water (10-25ml), product was extracted with an organic solvent (i.e. ether, DCM or chloroform) and dried over Na₂SO₄. The organic layer on evaporation gave the desired amino derivative. Some products were directly converted into the HCl-salt with ethereal-HCl without evaporation of ether layer."

(from: A General Procedure for Mild and Rapid Reduction of Alipathic and Aromatic Nitro Compounds Using Ammonium Formate as a Catalytic Hydrogen Transfer Agent, Tetrahedron Letters 25(32), 3415-3418 (1984))

And the idea of azeotropically drying a solution with an apropriate solvent (toluene, benzene etc.) isn't that wierd like SWIA first thought: its in this thread, Barium uses it here Post 384333 (Barium: "Dare I say quantitative yield", Novel Discourse) to remove water from post-cth mixture with toluene, but he used a rotovap, seems as if normal distillation does no good to freebase amphetamines in this case... frown
Barium, do you think that not acidifying before removing the solvent/alcohol reduces yield? (->steam distillation?)
Or perhaps basifying everything bee4 the first extraction would be good? SWIA was under the impression that the mixtr. was nearly saturated with ammonia, but I think the yield could be raised quite a bit with some modifications... freebase looked REALLY nice, clean, bright - BEFORE SWIA reduced the volume of its solution... mad and I think the procedure could surely be modified to give good purity AND good yields - but how?

To Ganesha: Scrape matchbooks, hm? tongue

armageddon
(Hive Bee)
04-22-04 14:01
No 502244
User Picture       halogenation?

Hi!

The FSE is still down ( shocked ), so I have to reply to myself because of not being able to find a better thread...
..sorry.

I wonder if one could avoid the use of borohydride if the nitropropene was chlorinated before doing a CTH.
The chlorine ion adds to the beta-carbon, replacing the double bond. As this rxn is reversible, acidic medium would be required (thx for pointing me to that, nicodem smile ) to prevent the chloro-nitropropane intermediate from being dehalogenated again.
But acidic environment would interfer with the use of ammonium formate as hydrogen donor.
I'm a bit usure whether ammonium ions are useful in this CTH reduction, but the use of ammonium chloride (stable in HCl) would help if this was the case.
Question: how does formic acid behave in dil. HCl solutions? It would give a nice hydrogen donor, while maintaining acidic conditions.
And I don't think it will, but just to be sure: HCl isn't decomposed to hydrogen and chlorine (cough!) by Pd/C, is it?
I know nitropropenes can be reduced by halogenation at the beta-carbon (with HCl(g)) and dehalogenation/reduction with Pd/C and hydrogen under pressure, so I started wondering if it could be possible to use the technique of halogenating nitroalkenes in a CTH reduction...

(operating with vessels under pressure with hydrogen/HCl(g) isn't my thing laugh )

Any comments, thoughts, critique?

Greetz A

"..ein Trank von unterschiedlicher Farbe, in ihm ist Heilung für die Menschen."

Nicodem
(Hive Bee)
04-22-04 22:37
No 502328
User Picture       I wonder if one could avoid the use of ...

I wonder if one could avoid the use of borohydride if the nitropropene was chlorinated before doing a CTH.

If it works with H2 there is a good chance it will work in a CTH reaction as well. Assuming, off course, that you use a hydrogen donor usable in a highly acidic environment (no, ammonium formate won't work - there are other hydrogen donor besides this one). And I assume you are talking about hydrohalogenation and not chlorination as you wrote. This hydrohalogenation or Michael addition of HCl (for some historical reasons also called Antimarkovnikov addition of HCl) is not the same as chlorination (addition of Cl2)!

I'm a bit usure whether ammonium ions are useful in this CTH reduction, but the use of ammonium chloride (stable in HCl) would help if this was the case.

Maybe you could at least explain how you think ammonium ions can be useful in a CTH reduction. What you need is a hydrogen donor, something like the formate anion, hypophosphite anion, hydrazine, cyclohexene, isopropanol or whatever that can donate a hydrogen at the given conditions (acidic in your case).

Question: how does formic acid behave in dil. HCl solutions? It would give a nice hydrogen donor, while maintaining acidic conditions.

It sucks. Formic acid is poorly dissociated compared to the practically fully dissociated ammonium or potassium formate. If you add HCl to formic acid it will shift the dissociation equation even more to the left leaving even less (read as "no") formate anions for the CTH.

I know nitropropenes can be reduced by halogenation at the beta-carbon (with HCl(g)) and dehalogenation/reduction with Pd/C and hydrogen under pressure

Who told you that you need pressure? If plain nitrostyrenes reduce under atmospheric pressure, why should phenylnitropropenes need more pressure? Maybe they do, but I would at least try at normal pressure before claiming that. And if you have the same paper in mind as I do, it is not HCl(g) but conc. HCl(aq). If otherwise please give me the ref because I did not read that yet.

“The real drug-problem is that we need more and better drugs.” – J. Ott

armageddon
(Hive Bee)
04-23-04 02:50
No 502388
User Picture       changing refs

Hi Nicodem!

The reason why I stick with my ammonium ions is because Post 335851 (Sunlight: "MDA and MDMA from CTH reductive amination", Novel Discourse) reduces ketones with ammonium formate AND ammonium acetate and Post 477266 (Lego: "Reduction of oximes with zinc/ammonium formate", Novel Discourse) posted an article stating that ammonium chloride can be used (longer rxn time) instead of ammonium formate in the reduction of alipathic nitro compounds. (So I think ammonium ions can be hydrogen donor, too...)
And as there are different theories about the intermediates involved in cth reductions, I thought an ammonia releasing hydrogen donor could be useful when reducing nitro group via cth - perhaps the ammonia helps forming one of the better reducable intermediates? (at least it doesn't interfer with CTH).

The paper I meant only says a few sentences about hydrohalogenation (you're right, oops) and reduction via pd/c-H₂. You can find it here: Patent US6399828 (for me this link didn't work, here's another one:)
http://l2.espacenet.com/dips/viewer?PN=US6399828&CY=gb&LG=en&DB=EPD

But as I read it I realize it says "Chlorination of norephedrine with thionyl chloride, followed by catalytic hydrogenation of the resulting hydrochloride, gave amphetamine."
Anyway, chlorination of a -OH group or hydrochlorination of a C=C bond - the result is the same, isn't it?

I wonder how they managed to isolate the hydrochloride of phenyl-1-chloro-2-aminopropane?

Damn, THAT would be nice! If the intermediate chloropropane could bee isolated, NO acidic CTH environment would be needed (perhaps slightly acid, GAA should solve that)!

Oh, please tell me: how could I reduce a nitroalkene "without any pressure" but still with hydrogen gas? Or did you mean regular CTH? Every catalytic hydrogenation I know that yields amphetamines (RaneyNi, Pd/C) requires at least 1 atm pressure to work properly..
(maybe thats different with nitrostyrenes, but they need no borohydride reduction of any double bond at all, since they are readily reduced to phenetylamines for example by regular CTH.. I think about hydrochlorination of nitropropenes as a cheap substitute for borohydride)

Greetz A

"..ein Trank von unterschiedlicher Farbe, in ihm ist Heilung für die Menschen."

Nicodem
(Hive Bee)
04-23-04 16:11
No 502482
User Picture       Mixing up everything you can?

Your reasoning about why you like the ammonium ions to be present in a CTH reaction makes no sense whatsoever. Again you are comparing two completely different reduction reactions that cannot bee compared. CTH reduction is not the same as a metal dissolving reduction! You don't need acids like NH4⁺ in a CTH system to get it run. On the contrary, what you need is a CTH reduction system that still works in a HCl acidic system. There is absolutely no reason whatsoever to add additional acids.

So I think ammonium ions can be hydrogen donor, too...

Could you please explain how do you expect NH4⁺ to bee a hydrogen donor. Are you implying that at the given conditions it decomposes to H2 and N2? Though this is a theoretically possible reaction it is not going to happen. If you have hydrazine in mind, then yes, hydrazine is an excellent hydrogen donor, but hydrazine is not ammonia. Or maybe you simply confused proton donor (which NH4⁺ is) with hydrogen donor - these are two completely different things.

Anyway, chlorination of a -OH group or hydrochlorination of a C=C bond - the result is the same, isn't it?

No. The methylamino is not the same as a nitro group. The difference is so enormous that I’m not willing to loose time explaining.

I wonder how they managed to isolate the hydrochloride of phenyl-1-chloro-2-aminopropane?

What’s to wander here? As long as the amino group is protected as its hydrochloride the "chloroephedrine" is a perfectly stable compound. It is only in its freebase form that it decomposes to the aziridine derivative. And if the aziridine forms during the CTH it is by no mean a problem because its reduction product is still methamphetamine.

Oh, please tell me: how could I reduce a nitroalkene "without any pressure" but still with hydrogen gas?

I'll not say UTFSE since it is down. I'll say: "use the search engine at the Rhodium site and you will find the paper you need." I can't understand how can you all the time talk about a procedure about which you obviously did not even read the original literature so far. I can't believe that you want to modify a hydrogenation reaction that you did not even read about so far into a CTH reduction. What's wrong with reading? If the libraries scare you, there are still many papers here on The Hive and at Rhodium's home page that you did not check.

Every catalytic hydrogenation I know that yields amphetamines (RaneyNi, Pd/C) requires at least 1 atm pressure to work properly.

1 atm is the normal atmospheric pressure (hence the name atm from atmosphere – 1atm=1,01325bar=760torr=14,6959PSI=101325Pa). Anything less than 1 atm is considered reduced pressure or under pressure and requires a vacuum pump or, since we are talking about H2 partial pressure, mixing of H2 with an inert gas.

“The real drug-problem is that we need more and better drugs.” – J. Ott

armageddon
(Hive Bee)
04-24-04 00:11
No 502577
User Picture       Hi Nicodem! Nope, I talked just about a CTH...

Hi Nicodem!

Nope, I talked just about a CTH for dehalogenating/hydrogenating phenyl-1-chloro-2-aminopropane. I didn't mix up CTH and dissolving metal reduxn. Maybe NH₄⁺ doesn't release hydrogen, but can you say for sure that it is of no advantage? Do you know that there isn't any intermediate compound formed with CTH that would profit from ammonium ion presence (like maybe a ketone) and would get reduced faster? I don't know.

I don't wonder if it's possible, I just would like to know how they did isolate the chloroephedrine. The procedure. Writeup. Anyway.

Methylamino is absolutely not nitro, but where is the methylamino in phenyl-1-chloro-2-aminopropane?? Or the nitro group? (OK if you spell it 1-phenyl-1-chloro-2-methylaminoethane then there is a methyl present, but a nitro?)
I wanted to say: the resulting product (said chloropropane) has the same Cl-ion attached at the first carbon seen from the aryl - if you chlorinate an OH-amino-compound or if you hydrochlorinate a "Ar-C=C(CH₃-(nitro)" doublebond (at least in this case). BTW I don't see any methylamino group, just a 2-aminopropane chain with extras smile . Of course, if you think in styrene terms... well.

But I think Pd/C doesn't care whether it has to do additional work reducing NO₂ or whether the amino group is already present. In both cases, it has to dehalogenate (almost) the same phenylpropane - at the same carbon. (Just look at page 2 of the ref I gave u, there's a nice picture, you can see that SoCl₂ chlorination of norephedrine results in the same compound as does hydrochlorination of P2NP, only difference is the nitro group. The intermediate is a primary amine...)
I wonder if said HCl+P2NP occurs too when doing a SnCl₂/HCl reduction to the ketone?

Oh, and I know the catalytic hydrogenation procedures described at rhods archive. (At least the standard ones smile )

Did you know "under pressure" also means "with pressure" or pressure above 1 atm?

I would like to see you performing a catalytic hydrogenation with something like argon/hydrogen (3:1 maybe?) and 100 mbar "under pressure"??

Peace A

"..ein Trank von unterschiedlicher Farbe, in ihm ist Heilung für die Menschen."

Nicodem
(Hive Bee)
04-24-04 13:40
No 502666
User Picture       For the last time

Nope, I talked just about a CTH for dehalogenating/hydrogenating phenyl-1-chloro-2-aminopropane.

Really!? Post 477266 (Lego: "Reduction of oximes with zinc/ammonium formate", Novel Discourse) is about a metal dissolving reduction! I really don’t understand how can you see any similarity between the reductions with HCOO^-/Pd-C and Zn/NH4⁺. These are two completely different methods with different mechanisms. Maybe this is the problem. You should first understand the underlying mechanisms and than make your claims. Doing the reverse helps just nobody.

Do you know that there isn't any intermediate compound formed with CTH that would profit from ammonium ion presence (like maybe a ketone) and would get reduced faster?

What can any reduction intermediate gain from an inert ammonium cation in an acidic medium? This is almost as absurd as proposing Na⁺ to aid the reduction.

I just would like to know how they did isolate the chloroephedrine

You also made the same mistake as I did in the last post - it’s norephedrine and not ephedrine. Anyway, they never isolate the “chloronorephedrine”. Like I already explained you, it is not possible to isolate it as it starts decomposing as soon as it is formed. That is why they use its hydrochloride salt which is stable due to the amino group protection. Besides, what would they want to isolate it for anyway? Please, read the patent again!

Methylamino is absolutely not nitro, but where is the methylamino in phenyl-1-chloro-2-aminopropane?

Like I said I thought the patent used ephedrine (= 1-phenyl-2-methylamino-propanol).
Look, you really cannot compare your 1-phenyl-1-chloro-2-nitropropene with this “cloronorephedrine”. The amino group has practically all the properties diametrically opposite to the nitro group. And the decomposition reactions of the two compounds are very different yielding two completely unrelated types of compounds:

Ph-CHCl-CH(NH2)-Me <=> Ph-CH-NH-CH-Me Ч HCl
Ph-CHCl-CH(NO2)-Me <=> Ph-CH=C(NO2)-Me + HCl

While the aziridine of the first reaction can still be reduced to the amphetamine by CTH the phenylnitropropene can’t be.

Anyway, I give up. I can’t communicate with someone who only read and see only what he what to read and see. You only make me repeat myself which is very frustrating. Everything you wanted to know was explained, now it is up to you to read everything again and try hard to really understand. I can only suggest you to study more, go to the library, do some literature search and take some time for the chemical theory before you do laboratory work.

“The real drug-problem is that we need more and better drugs.” – J. Ott

armageddon
(Hive Bee)
04-25-04 00:34
No 502762
User Picture       Wow! Great help!

Hey, I just wanted to know if there are chances that hydrohalogenation of a nitropropene, followed by CTH in acidic media (or hell, any other useful reduction) with an apropriate hydrogen donor being stable in acidic conditions (which are needed to prevent shifting back to the nitropropene) could work. Also I wanted to know which CTH hydrogen donors are stable in dil. HCl.
The reason was to avoid using borohydride to reduce the double bond of alkenes...

Quoting each of my words and criticizing/correcting every statement isn't really helpful - and I don't see why you question every thing I say - it's not all wrong. I just talk about things I read about before.
And since in the patent they perform a pressure hydrogenation anyway, why should they be concerned about protecting or halogenating any amino or hydroxyl group in order to prevent nitropropene formation? Pd/C hydrogenation under pressure also works on nitropropenes directly, not only with halogenalkane*HCl complexes...

(C'mon, show me where you read that they did NOT isolate the HCl salt! Do you think they write everything with a " * HCl" because wanting to say all rxns are carried out in acidic media? I thought it meant forming hydrochloride complex salts... usually a method of purification!)

Quote: "By another procedure, heating norephedrine with thionyl chloride at reflux temperature, followed by catalytic hydrogenation of the resulting 2-amino-1-chloro-1-phenylpropane hydrochloride, gave amphetamine." (and I think they meant hydrogenation with more than 1 atm pressure, not below 1 atm, BTW)

Oh and a last thing: there is also a reduction method using plain sodium and alcohol I think - Na⁺ as reducing agent being absurd? I don't know if that's true.

(next time, just say "Don't think this will work", instead of telling me I'm such an idiot contrasted to you being SOO clever, ok? That should suffice, too!)

"..ein Trank von unterschiedlicher Farbe, in ihm ist Heilung für die Menschen."

Rhodium
(Chief Bee)
04-25-04 03:55
No 502778
User Picture       Read up on your chemistry first, THEN post

Oh and a last thing: there is also a reduction method using plain sodium and alcohol I think - Na⁺ as reducing agent being absurd? I don't know if that's true.

"Plain sodium" (the metal) is Na, not Na⁺ - the latter is a sodium ion, which is ridiculously inert. You cannot reduce anything with Na⁺.

Armageddon: I don't want to see any flamewar in this thread, so quit arguing when you have no hard data to back up your statements with. I'm sorry to have to tell you this, but Nicodem is right in what he is saying above, and you have several inconsistencies and factual errors in each of your posts above.

^{The Hive - Clandestine Chemists Without Borders}

	https://the-hive.archive.erowid.org	the-hive@erowid.org



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