qt314
Harmless
Posts: 12
Registered: 25-1-2019
Member Is Offline
|
|
3,4,5-trimethoxyphenylacetonitrile hydrogenation problems
Hello. I havent posted here in a *very very* long time but find myself in need of help ...
I have been trying to reduce 3,4,5-trimethoxyphenylacetonitrile to the amine. I have employed several methods and encountered problems throughout.
At first I followed the general protocol with CoCl2/NaBH4 (0.1eq/2eq) with thf/water
Results were acceptable at the beginning, roughly 50% yield.
I then moved to IPA/water (I try to avoid thf when I can). Just replacing the thf with IPA gave comparable results.
During optimization studies I reached 90% yield twice by employing reverse addition (borohydride in ipa/water, nitrile added slowly). Apart from these
2 experiments, all times yield was consistently 20-30%.
So, I moved to (20% w/w with nitrile) Pd/c and hydrogen gas under balloon pressure with 1-2 eq of mineral acid.
Best yield so far is 35% after 8 hours. 48 hours gave 10%.
I am at a loss. The nitrile is clean (98.28% assay, nmr is perfect), solvents are clean, palladium is of good quality ....
Can anyone advise or give tips?
|
|
|
myr
Harmless
Posts: 48
Registered: 18-7-2018
Member Is Offline
|
|
Tetrabutylammonium borohydride will work (but doing so is 100% illegal.)
|
|
|
qt314
Harmless
Posts: 12
Registered: 25-1-2019
Member Is Offline
|
|
TAB witg CoCl2 should work though I haven't tried yet. Or do you claim it works without the cobalt?
|
|
|
qt314
Harmless
Posts: 12
Registered: 25-1-2019
Member Is Offline
|
|
Oh, forgot to mention - I tried cth with ammonium formate and pd/c (6eq, 20% w/w respectively) for 12 hours = ~30% yield
|
|
|
unionised
International Hazard
Posts: 5102
Registered: 1-11-2003
Location: UK
Member Is Offline
Mood: No Mood
|
|
Just a thought; O2 goes through rubber quite well
|
|
|
qt314
Harmless
Posts: 12
Registered: 25-1-2019
Member Is Offline
|
|
So, you think that a long time with a balloon may let O2 in and inhibit reaction?
I have been using double layered balloons quite well for hydrogenation of other compounds and it works quite well
|
|
|
clearly_not_atara
International Hazard
Posts: 2692
Registered: 3-11-2013
Member Is Offline
Mood: Big
|
|
What kind of mineral acid are you using? The studies I see use sodium dihydrogen phosphate. I get the feeling an excessively strong acid will
hydrolyse the nitrile.
https://www.sciencedirect.com/science/article/abs/pii/S09268...
| Quote: | | During optimization studies I reached 90% yield twice |
This was not reproducible?
[Edited on 04-20-1969 by clearly_not_atara]
|
|
|
qt314
Harmless
Posts: 12
Registered: 25-1-2019
Member Is Offline
|
|
I am using HCl (37%, AR). Some hydrolysis does take place. I do the reaction in an ice/salt bath - the rate of hydrolysis is not that big. Using
sodium dihydrogen phosphate does make sense. I will give it a try tomorrow.
I today noticed that the solubility of the nitrile drops appreciatly when the acid is added, which may account for my low yields. I am testing this
hypothesis now.
Regarding the CoCl2/NaBH4 - I dont know what to say. I am not able to reproduce these results no matter what I try. It is very weird. TLC shows either
of 2 results -
Case A - ~50% of nitrile reacted, ~30% primary amine product, the rest being secondary and tertiary amines.
Case B - ~75% of nitrile reacted, major product is unknown, runs very very close to the nitrile. ~25% primary amine yield.
These results repeat no matter what variation I take (more borohydride, different solvents, different temps, different concentrations, different
reagents).
The 2 times 90% primary amine yield was achieved tlc showed a very clean reaction, mostly primary amine, some leftover nitrile, some tertiary amine.
For the life of me, i do not know what to make of this.
|
|
|
S.C. Wack
bibliomaster
Posts: 2419
Registered: 7-5-2004
Location: Cornworld, Central USA
Member Is Offline
Mood: Enhanced
|
|
Quote: Originally posted by qt314  | | During optimization studies I reached 90% yield twice by employing reverse addition (borohydride in ipa/water, nitrile added slowly). Apart from these
2 experiments, all times yield was consistently 20-30%. |
Doesn't it sound like a lower concentration of nitrile and intermediates and/or lower temperature is helping? Dimerization is expected to be a problem
even more so with phenylacetonitriles, which may explain the unpopularity of this route to PEAs (by amateurs). PS instead of increasing the
borohydride it would not be uninteresting to increase the Co from those low levels and see if perhaps a larger amount of the boride is a good thing.
[Edited on 28-1-2019 by S.C. Wack]
|
|
|
qt314
Harmless
Posts: 12
Registered: 25-1-2019
Member Is Offline
|
|
| Quote: Originally posted by S.C. Wack | | Quote: Originally posted by qt314 | | During optimization studies I reached 90% yield twice by employing reverse addition (borohydride in ipa/water, nitrile added slowly). Apart from these
2 experiments, all times yield was consistently 20-30%. |
Doesn't it sound like a lower concentration of nitrile and intermediates and/or lower temperature is helping? Dimerization is expected to be a problem
even more so with phenylacetonitriles, which may explain the unpopularity of this route to PEAs (by amateurs). PS instead of increasing the
borohydride it would not be uninteresting to increase the Co from those low levels and see if perhaps a larger amount of the boride is a good thing.
[Edited on 28-1-2019 by S.C. Wack] |
Lowering the nitrile concentration has crossed my mind. I will try it.
Increasing the Co eq does indeed improve things considerably but it becomes uneconomic... BTW, Co boride can be supported on carbon easily and gives
for me comparable yields to unsupportee Co (this simplifies workup considerably).
Low temperatures (as in, lower than 10C) will halt reduction and only allow for hydrogen generation through catalysed borohydride hydrolysis. Too high
temperatures increase the rate of borohydride hydrolysis too much also (above 55C ime).
While dimerization does pose a real problem, in theory hydrogenation of nitrile is straightforward...
I was thinking of trying carbon supported Co boride under hydrogen atmosphere with ammonia according to Barnett (https://doi.org/10.1021/i360030a009) but I insist to avoid pressurised hydrogen reaction so it remains to be seen if balloon hydrogen will be
sufficient. Ill post results
|
|
|
qt314
Harmless
Posts: 12
Registered: 25-1-2019
Member Is Offline
|
|
--update--
I followed the progress of reaction on tlc (MeOH/Conc. Ammonia, 100:1) every hour instead of checking after 12 hours on all my experiments due to
error in my logic regarding the time required for completion.
After about 5 hours ~10% starting nitrile remains, only primary amine product is formed. 1 hour later secondary amine product begins to accumulate and
most of nitrile is gone.
Workup gave 70% molar yield of primary amine hcl along with ~20% of secondary amine.
Reaction conditions were :
300ml MeOH, 7.5g 37% HCl, 6g pd/c 10% (60% water content), fitted with hydrogen balloon. Reaction was conducted in an ice bath on a magnetic stirrer.
Can still optimize a bit, but im pleased with the results 
|
|
|
![[*]](images/xpblue/default_icon.gif){kind=icon}
