The CTH Writeup by Barium as Tried Out by Bandil. Sciencemadness Members Clear Things Up!

Oh my

I imagine that Sauron asked because of the way you phrased all this.

Forum researchers can easily be wrong (especially those who dose themselves with reaction products ). Peer-reviewed research chemists can be wrong. Patent chemists can be wrong, and even prone to mislead.

This procedure was written by a respected researcher, uprated to "excellent," and praised by several very intelligent members. Its basis in literature was clearly documented.

By employing "fake," "by any and all means fake," "wannabe chemists" you imply deceit—an intention to create something not genuine—and ineptitude. If you insist upon such incendiary language, you should probably: a) make sure you are right, b) familiarize yourself with the theory of the reaction to make sure your polemic makes sense, c) provide details of your process, if only to confirm that you followed it correctly, and d) try at least to provide accurate documentation (get the author right).

Or just try to use words like "incorrect" instead of "fake." And don't insult established members of the community, even if they make a procedural error.

Don't get me wrong, this procedure might not work after all. But based on your errors, absence of detail and lack of research into this reaction I'm going to assume that you don't know enough to say with so much certainty that the fault is with the procedure, and not your execution of it.

If you asked a question, someone with more knowledge might be able to help you out.....

The "writeup" in question

Ah. Details are good!

CTH succes

Barium's CTH method was tried with succes..

Nitrostyrene was made using GAA/Cyclohexylamine with 78% yield, and recrystallized with MeOH to afford nice yellow plates, single spot on TLC.

Nitroalkane was made by Barium's EtOAc/EtOH borohydride reduction, using 4 equivalents, and was isolated and recrystallized twice from MeOH to give beautifull colorless needles, with an overall yield of 82%, single spot on TLC. A few mishabs during recrystallization must have causes some mechanical losses (The solvant system MeOH/H2O was tried, but resulted in the nitroalkane oiling out during two attempts, so solution had be diluted, extracted, and solvant removed again, two times.)


CTH reduction

0.17g of 10% Pd/C (Acros) were suspended in a little abs EtOH and pipetted into a schlenk under Argon, with magnetic stirring.
15 mL of abs EtOH were added with a syringe, followed by 7mmol of solid nitroalkane, under slight stirring.
3.00g (35.67 mmol) of solid HCOOK (very hygroscopic!) were added followed by 1,7mL (95.24 mmol, 2.67eq) of H2O, which caused immediate evolution of H2, and solid KHCO3 appeared.

The schlenk was fitted with a condenser and placed in a 50°C oil bath, and stirring increased, the gas evoltuion (monitered by a wash bottle connected to the top of the condneser) increased too, the stream of Argon was cut.
Small quantiites of GAA were added via syringe when the black suspension became too thick to be properly stirred. The oil bath was gradually increased to 78°C, a mild reflux set in.

After 5h of reflux, the mixture was much more fluid and gas evoltuion had practically ceased. (It had drasticly dropped after about 2h). The oil bath was removed, and the schlenk left to cool under Argon.
GAA was added under stirring in a ice bath until acidic (10mL, large excess) and the catalyst was vac filtered over normal filter paper, refiltered on the same filter to clear up the slight purplish tint. The solution came out crystal clear after the second filteration. The catalyst was washed with 10mL EtOH and 10ml H2O which where combined to the original filtrate. The catalyst was regenerated, see at the end.

The EtOH was distilled under light vacuum, at 45°C, until only water started to pass. The 30mL residu was diluted with 20mL dH2O, and washed with 2x15mL of DCM. The first wash had a amber tint (unreacted nitroalkane?), the second was clear.
The aq. was delicatefully basified with 20% NaOH, with 20mL DCM. The addition of the base caused cloudiness and an clear oil crashed out. As soon as the cloudiness persisted, the pH was > 10. The DCM was seperated, and the aq. extracted with anothenr 2x20mL DCM.
The combined organics where washed with 2x25mL brine, dried, and the solvant was removed, the water-clear oil remaining was left under vacuum to evaporate the solvant remains.

The amine base was diluted in10mL abs EtOH, and titrated with shaking with freshly prepared 10% w/vol H2SO4 in EtOH. This caused immediate precipitation of a white solid. The pH was frequently checked with dampened pH paper, and titration stopped as soon as pH was acidic.
The white solid was vac filtered, washed with 10mL EtOH and 10mL anhydrous acetone, and dried under a lamp, to afford the amine in a yield of 62%.

catalsyt regeneration

Following US3214385, the catalyst was washed with 100ml of 10% NaOH, passed two times, then with ~50mL of dH2O until the washes had a pH of 8.5. It was then dried under suction for 15min, and placed in a vial under argon.

Comments

The substarte was a sensitive one, but still gave very respectable yields, so this methods definatively works

Even if certain of Barium's methods haven't always been reproductible (Thinking of the "wet reductive alkylation" with NaBH4 which I've personally never seen/heard to give acceptable yields except by the author and another few), this one seems to be a efficient one. Few parameters could be modified to obtain excellent yields IMHO.

It's surprising that just by changing to order of introduction of the reagents Stoechimetric_Steve passed from failure to succes, alot of parameters could count.

BTW, I really recommend isolating and recrystallizing the nitroalkane between double bond reduction and CTH, the intial yellowish oil that solidifed quickly contained some colored impurities that could possibly mess up the catalyst or interfer in one way or another. By recristallzing the nitroalkane (if it's a solid!), on get's a pure product easily.
The final product will also be recrystallized although it seems to be very pure. The method of forming the sulfate salt, although satisfying, may not be the more efficient solvant-wise. The filtrate will be evaporated to check if any dissolved product is present. IPA or perhaps AcOEt could easily substitute for EtOH.

I don't know how vital the Argon atmospher is, but I prefer using it when I can, especially with the catalyst at the beggining; the gas evolution during the reaction, if some sort of bubbler is used, prevents any air to come in on it's own.

I also don't know how effective the regeneration of the catalyst is, I'll try it some day to see. Unfortunaly, it contains some filter paper fibres as it was scrapped off, I'll just compensate the weight next time I use it. Harder filter paper, or celite would be more avantageous i guess.

[Edited on 28-8-2007 by Klute]

I think we can agree that isolating and purifying the intermediate nitroalkane is a necessary step to obtain descent yields...

If the nitroalkane is a liquid and a strong vacuum isn't availble, at least a few washes would be needfull IMO.

PS: I think the title could be changed

[Edited on 28-8-2007 by Klute]

Experiment 1:

9g of wet (probably 25% H2O) 10% Pd/C was introduced in a 3-neck 500ml RBF equipped with reflux condenser and an overhead stirrer.

150mmol of a previously distilled substituted phenyl-2-nitropropane (a water-clear liquid with a very slight pinkish tint) was added to wet the catalyst.

270:30ml MeOH:H2O and 50g NH4COOH was added, stirring started, the mix was flushed with Argon (which produced the strange fumes mentioned above, by apparently displacing some gaseous material dissolved in MeOH) and 34g HCOOH 98% was added dropwise over the course of the reaction (1 drop every ~20 secs).

the reaction was allowed to stir for 24 hours.

addition of a bit of 20%w/w H2SO4 caused CO2 evolution and a white, flaky, voluminous precipitate appeared (this is your product!) which dissolved upon addition of water.

the workup should be done like this:

Filter the reaction mix through coarse filter paper twice without acidifying. rinse the filter cake generously with MeOH and add the washes to the main filtrate.

the precipitate in the filter will be washed away with dH2O and kept separately.

the main MeOH/H2O filtrate probably needs to be filtered once more on fine filter paper which removes the rest of the suspended catalyst.

the catalyst wasn't regenerated as in previous runs, it was rinsed with MeOH and a bit of 20%w/w H2SO4, scraped from the filter paper with a spatula and put in a small bottle. the filter paper, to which a lot of catalyst still stuck, was suspended and stirred with 3x 10ml dH2O to wash out some more catalyst. this method produces a ready-to-use mix of catalyst along with the amount of water needed for another 150mmol batch. to get all of the catalyst out, the bottle can be rinsed with MeOH.

acidify the filtrate and remove the MeOH in vacuo. combine both filtrates (make sure the combined filtrates are now acidic) and extract 3 times with toluene (or something that pulls shit equally good...i just love it). basify and extract 3 times with toluene. dry toluene with Na2SO4, remove toluene in vacuo et voilà!

i didnt get as far as to remove the toluene since it was pretty late already - so i dont know any yields. but: upon adding NaOH (aq. ~25%), there were heavy milky clouds with droplets about 1mm in diameter rising to the liquid surface, forming a separate layer approximately 2mm*55mm²*pi = ~19ml . the freebase will be saved and distilled after another verification batch with the recycled catalst has been run.

happy birthday.

That looks good

One question: Why do you (and alot of other writeups) acidify after you have filtered the catalyst?
Why not add dilute acid, a little water to dissolved any eventual precipitated product, filter and then strip the alcohol? I personally always feel more confortable with the product as an salt doing work up, except when it's diluted in non-polar solvants of course.

I guess it less troublesome when using NH4OOCH, but with HCOOK, the solid KHCO3 could retain quite some product, even with a few alcohol washes (which are going to be distilled afterwards), but if you acidify before filtering, you only have the fine catalyst to filter, and you have a fairly concentrated aq. solution of the potassium salt of whatever acid you used to acidify wich makes work up easier IMHO. Evaporate alcohol under slight vacuum, and when take off reduces and there's alot of bumping (as while trying to remove water from a concentrated solution of MeNH2.HCl or HCOOK, you get the idea), perform an A/B, evaporate solvant, crystallize to your favorite salt, et voila.

Just my two (euro ) cents

it seems that the post reaction mix when using NH4COOH is in fact a basic solution with the alkylammonium carbonate salt dissolved, so there is simply no point in acidifying at all. it just increases the volumes to handle. i need to give the reaction a second shot, but as far as i can remember, the was no precipitate whatsoever before i added acid.

so basically, you would take the post rxn mix, do the workup as above and DO NOT acidify when you remove the MeOH in vacuo.

the acidification step is probably introduced to minimize losses due to the volatility of the amine, it being able to be distilled with steam.

the solution to your problem is: use NH4COOH. i dont know what the deal is with KCOOH, it is more expensive, you have to make it yourself, it is very hygroscopic and insoluble in alcohols. what do i care if someone says it is a better hydride donor?

the ~25ml of slightly gold tinted freebase i got from the above attempt is, if i dare say that, as good as it can get. fack KCOOH

edit: a quick check was done, proving myself wrong thinking that dissolving amine freebase in acetone would form an imine: the addition of 6M H2SO4 in Et2O caused instant deposition of a bright white precipitate.

[Edited on 30-8-2007 by stoichiometric_steve]

Well great, no need of scanning the article

I didn't realize you conducted the reaction at room temp! That's something solved...
And yes, I only flush the flask at the beggining, leave a little stream when the reagents are introduced, and then shut it off. Argon is expensive, I'm not to keen on sending some in the atmospher just for the sake of it

I frequently neutralize the bicarbonate with GAA, but it could effectively cover some catalyst surface... And the problem of reteiving palladium in the final salt mentionne din the article isn't too reassuring..


You've convinced me, I'll give ammonium formate a try on of these days!

80% molar yield after distillation of the base from the 150mmol batch (see writeup above). very cool best workup ever!

85% molar yield after distillation from a 268mmol batch, using 15% w/w 10% Pd/C catalyst.

take my word: keep water out of the workup until you get to the a/b purification, and you will be a happy chemist.

[Edited on 21-9-2007 by stoichiometric_steve]

Dear klute,
I've been busy on this subject A LOT lately.
About the nitroalkene it runs completely to the top with pure ethylacetate and also with DCM/MeOH (98% DCM, 2% MeOH) on TLC. See if that yellow crystals do this or stay at the start, that's already a conclusion if it are salts or an organic compound.
Look at solubility in water and in MeOH, for the furtherrest try to make an IR of it.
And something interesting for everyone SWIM tried Pd/C with HCOOH and Et3N.
It works like a charm, it gives really great yields. And if anyone is looking for the paper where a lot of people are refering to when doing NaBH4 reductions I can upload it if there is interest for it.
This is the one.
Sodium borohydride reduction of nitrostyrenes by Reverse addition: A simple and efficient method for the large-scale preparation of phenylnitroethanes.
Synthesis, 1985, 9, 886-887
... has been fucking around with reducing nitrostyrenes to nitroethanes and also got moderate yields, but now when using this paper, yields are great .
And ANOTHER interesting thing, reducing nitrostyrenes directly to the amine with Fe/HCl.
Also got the paper about that one, also worked but in like 65-70% yield.

[Edited on 3/3/2008 by Nicodem]

Quote:

Originally posted by DNA Sodium borohydride reduction of nitrostyrenes by Reverse addition: A simple and efficient method for the large-scale preparation of phenylnitroethanes. Synthesis, 1985, 9, 886-887 SWIM has been fucking around with reducing nitrostyrenes to nitroethanes and also got moderate yields, but now when using this paper, yields are great

There are a few articles, being worth what there are, dealing with this, but they often use a equal weight of catalyst to substrate! That hardly is a catalyst anymore...

From the Rhodium Archive:

Synthesis of Phenethylamines by Catalytic Hydrogenation of Nitrostyrenes

Bull. Chem. Soc. Jpn. , 63(4), 1252-1254 (1990)

But again, all previous work from different forum mebers lead to think only the oximes where attainable. IIRC, a 2 step hydrogenation nitroalkene-->oxime--> amine was possible, but the catalyst had to be changed, and I even think that was with pressurized hydrogen.
Solo, if you are reading this, wasn't it you that tried that out?

So if the 1 atm hydrogenation can be succesfull, it would be good news! But to be honest, I remaing sceptical. No offense DNA, it just that there isn't much to back up such a possibly ground-breaking news.

[Edited on 4-3-2008 by Klute]

What amount of nitrostyrene did you start with? If you used 0.1-0.5g substrate, I can understand you used a large amount of catalyst... But even 0.5g is quite an amount, especially considering the price .

BTW, I have been kindly notifyed that catalytic hydrogenation of nitrostyrenes at 20-30°c and 60PSi with as less as 2% 5%Pd/C gives good yeilds in 2h. Obviously one needs a Parr shaker or similar device....

you shouldn't be

i've just tried out the method for the double bond reduction which uses Toluene/Water with a PTC (i used Aliquat 336), and it worked like a charm for 4-Fluorophenyl-2-nitropropene, which is usually a pain in the ass if EtOH/EtOAc solvent systems are used (because the nitronate crashes out and forms an intractable, gum-like mass that only very slowly dissolves in water - it can break your stirrer).

My guess is that this also works for Nitrostyrenes, since the PTC is supposed to carry inorganic anions (BH4- in this case) to the organic layer, and not the Nitrostyrene to the water phase where the nitronate resides. However, a lot of people got tarry product when using this method with all the Nitrostyrene added at once.
I used a Toluene solution of the substrate (1mol would need 450ml of Toluene) which was slowly added to the aqueous NaBH4 solution (~2eq. NaBH4) containing some NaOH to reduce decomposition.

The workup was incredibly easy...acidify (while cooling with ice!!!), separate the toluene, extract water layer with toluene and remove toluene. some unreduced substrate made it into the distillation flask and polymerized to a black mass upon heating. nevertheless, the distilled nitropropane was clean as fnack. i got 98%

[Edited on 31-3-2008 by stoichiometric_steve]

duh... of course how stupid of me. I'm a bit elsewhere lately
At what vacuum did you distill your nitroalkane, i get it the mentionned bp is that of the PTC (which did you use BTW: TBAB, CTAB?
How does the solvant volumes compare to the EtOAc/EtOH? (though i think i remember you said you never tried that system before.. not sure) Abs EtOH is time consuming..

CTH according to Pasad et al.

According to Pasad et al, article kindly posted by StoechiometricSteve in the first page of this thread, nitroarenes are quickly reduced in CTH conditions using formic acid and catalytic triethylamine. This forms triethylammonium formate in situ, which upon transfering hydrogene, forms free triethylamine and CO2.

Altough they add the formic acid in 30min, they exclusively use nitroarenes, which are known to react much faster than aliphatic nitroalkanes. Thus, when using nitroalkanes, it is advised to add the formic acid at a slower rate, to avoid acidic conditions.
StoechiometricSteve tried out a variation of this reaction, and told me that the reaction stopped if pH turned acidic.
I decided on trying this reaction out, but by using a larger amount of triethylamine, and adding the formic acid at a slow rate.

In the article, they claim that substrate or products that are basic enough to form formates can also act as a catalyst. When reducing nitroalkanes, the formed amines are often basic enough to enter this catalysis cycle. An interesting twist would be using a catalytic amount of product at the begging of the reaction!

2-MeO-nitroethane was used because it was in the fridge since a few months and i didn't have much use with it. It contained some dimer (obtained by naBH4 reduction of the nitrostyrene) as shown by TLC.

Catalytic TRansfert Hydrogenation of 2-(2-methoxyphenyl)nitroethane with formic acid and catalytic triethylamine




4.28g (23.91 mmol) of 2-(2-methoxyphenyl)nitroethane, a golden yellow viscous oil, was diluted with 10mL MeOH.
0.5g 10% Pd/C (Acros) were weighed and transfered to a 100mL 3-neck RBF flask, equipped with a condenser attached to a bubbler, a addition funnel, a thermometer and a stir bar. It was wetted down with 70:30 MeOH: H2O under a flow of argon. The substrate was added with 20mL more MeOH, under slow stirring. This formed a black suspension.






1,0 mL (7.21 mmol) of triethylamine (Acros) were added via syringe, and the flask was immersed in a 50°C oil bath.



4.6 mL (101.49 mmol) of 85% formic acid were then transfered to the addition funnel, and very slowly dripped in (1drop/40-50 sec). A slow, but constant gas evolution started. There was no bubbling visible in the flask. The addition lasted two hours. No change in apperance of the reaction medium. Heating and stirring were maintained for another two hours.

At the end of the addition, TLC (80:20:1 AcOEt:MeOH:Et3N) showed a large spot under the substrate, and only a small spot for the substrate. This could very well be the dimer, as it is not seperated from the nitroalkane with this eluant system.
After the two hours stirring, TLC had not changed.


[Rest when i get time to upload pictures]

Unfortunaly, because of a stupid mistake, the other photos were lost... In any case, the reaction medium didn't change apperance, and the workup was standard.


After 2 more hours stirring at 50°C, the flask was cooled down, and the black suspension filtered through two paper filter twice, giving a totally clear filtrate [Note 1]. The cake was rinced with 2x20mL MeOH, and 10mL 50:50 MeOH:H2O [Note 2]. The now slightly milky solution was acidified with conc HCl, causing the milkyness to increase. A little amount of clear, slightly yellow oil crashed out at the bottom.

The MEOH was removed at atmospheric pressure using a small coluum, until vapor temp increased over 90°C. The medium quickly took a blue (!) color upon heating, and most of the clear oil turned to a black/blue viscous residu [Note 3].
The solution was transfered to a sepperating funnel, and washed with 3x25mL toluene, which removed the blue color, but left a milky slightly amber aqueous layer. 20mL DCM wash removed a little of the color.
The aq was then basified with 15% NaOH slowly, causing strong milkyness and a clear oil to crash out. It was then extracted with 4x25mL toluene.
The combined opaque organics were thoroughly washed with 3x100mL 1% NaOH, which cleared it up pretty well, and 150mL brine, which gave a totally limpid, very slightly amber solution. This was neutralized with conc. HCl (>2.5mL needed) and transfered to a 250mL wide-neck distn flask. A little IPA was added to rince the erlenmeyer.
The IPA/Toluene/H2O azeotrope was removed by simple distn at atm, once all the IPA was removed, the distn setup was replaced by a Dean Stark, and reflux maintained until no more water was collected and the head temp exceeded 100°C [Note 4].
Upon cooling, the slightly orange solution was covered with a little pet ether, which caused alot of milkyness, and a whitish solid appeared.
After cooling to RT, the suspension was filtered, and the white solid washed with acetone to remove some orange gummy material, then with pet ether. It was dried by suction for 10min, then under a lamp to remove the solvant smell, then in a CaCl2 desicator. The crunchy cristalline mass weighed 0.94g (5.06 mmol) 21.07 % yield of 2-methoxyphenethylamine hydrochloride. The white crystals had a broad mp 139-146°C (but using a very artisanal method: oven and thermometer ), so it was not triethylammonium chloride (mp= ~240°C) [Note 5]

The catalyst was regenerated by thoroughly washing with fresh 10% NaOH, then with water, sucking air through it for 10min, and washing it with a little MeOH before leaving it dry overnight. It was easily scrapped off (though the filter paper obviously traps a certain amount). It is adviseable to use the weakest vacuum possible when filtering it to avoid excessive plugging.

Notes


Note 1: I have to agree with Steve now, there is no need to acidify before filtering when using (tetralkyl)ammonium formates. This was a much easier workup, and it avoids contaminating the catalyst with impurities comming from the acids (that's why i always used GAA and not technical HCl). But when there's bicarbonates around, i guess it's better to acidify to remove them from the catalyst.

Note 2: This was to avoid a eventual fire hazard: it's is a known fact that 10% Pd/C can spontaneously ignite when wet with MeOH after a reduction. The small amount of water prevents this, so the catalyst can be left on the buchner before being regenerated.

Note 3: I should have seperated what seemed to be unreacted nitroalkane before removing the MeOH... Heating for a certain period in acidic conditions must have caused all kind of side reactions... I guess adding dilute brine and a quick extraction before removing most of the MeOH would give less impurities..

Note 4: I'm not sure this is the best way for amine with ether groups: heating for a few hours (it is a long process) with excess acid at >100°C temp could cause some demethylation? But it is so practical.... Using vacuum or pet ether could help keeping the temp down. I should just gas some IPA with HCl i guess...

Note 5: The repeated water washes should remove small quantities of triethylamine quite easily (solubility : 7.5g/100g), but if using bigger amounts, it should be seperated from the amine freebase by vacuum distn, or at least leaving the freebase under high vacuum long enough to remove most of it without distn of the freebase itself.

Comments:

Well, the method surely isn't optimized for nitroalkanes yet. B ut it can be! I'm sure using at least 1 eq of triethylamine, or directly dripping 1 eq of triethylammonium formate, then 2-4eq of formic acid could be better, avoiding any acidic conditions, and ableing a quicker addition. The fact that there seemed to be no excessive gas evolution could mean no wasted H2.

Seems promising to me. Ok, you could just aswell tell me go buy some ammonium formate or stick to the potassium formate, at least you would get proper yields, but where's the fun in that? And in any case ammonium formate is too expensive for me to not consider anything else

RXN never took off

You could test your catalyst by adding a little formate solution to it, without any substrate, it should evolve some gas as Steve said. Better use a bubbler to really see the gas evolution, rather than looking for bubbles.

When you say your reaction never took off, does it mean you recovered your starting material quantitatively, or simply that nothing seemed to happen? As Steve explained, with saturated/activated catalysts, it seems only a true transfert hydrogeantion takes place, so no H2 evolution. Depending on your reaction temp, the CO2 evolution might be unoticeable. It seems if the catalyst isn't saturated, it first form nacent H2 from the donors, absorbs H2, and then reduces the substrate, so it's more of a dehydrogeantion/hydrogenation process.

Please giev use more details: what kind of substarte: alcene, nitro, etc, what solvent, temp, catalyst loading etc.

Be aware that most of the time, a CTH is just a black suspension, no excesive bubbling etc. It can look as nothign is happening, but that catalyst is doing his job well

Good luck with workup then

Apart from the price of Pd/C, this procedure is very easy to perform and employs cheap reagents. The workup is a breeze, and most of the time the yields go from good to excellent..

I think Steve has some experience with Zn/formate reductions of nitro compounds, and should be able to comment much more than me on that subject.

I've retried the CTH with 0.1eq Et3N, 5eq. HCOOH and MeOH:H2O 9:1. The bubbling effectively stops after about 2 hours, and a lot of substrate is still present by OC™ (Olfactory Chromatography™.

I'm currently looking into alternatives, but it turns out that Hydrazine, one of my favoured candidates, also turns out to be a catalyst poison under acidic conditions. This could probably be avoided by employing Hydrazinium Monoformate, discussed as a Hydrogen donor elsewhere (Tetrahedron 58 (2002):2211-2213)

just sayin'...this works beautifully on 1mol scale with NH4COOH/5%Pd/C