qt314
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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?
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myr
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Tetrabutylammonium borohydride will work (but doing so is 100% illegal.)
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qt314
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TAB witg CoCl2 should work though I haven't tried yet. Or do you claim it works without the cobalt?
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qt314
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Oh, forgot to mention - I tried cth with ammonium formate and pd/c (6eq, 20% w/w respectively) for 12 hours = ~30% yield
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unionised
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Just a thought; O2 goes through rubber quite well
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qt314
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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
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clearly_not_atara
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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?
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qt314
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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.
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S.C. Wack
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Quote: Originally posted by qt314 ![](images/xpblue/lastpost.gif) | 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]
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qt314
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Quote: Originally posted by S.C. Wack ![](images/xpblue/lastpost.gif) | Quote: Originally posted by qt314 ![](images/xpblue/lastpost.gif) | 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
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qt314
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--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
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