ChemistryAddictive
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Help with debenzylation of N-Benzyl
Hello,
i have some problem with debenzylation of N-benzyl protected amine.
I wanted to use a "Catalytic Hydrogenation" using 5% Pd/C + H2 in 50 C MeOH, but this requires 2 atm pressure, so to do this it's not a good option in
a simple glass flask.
I tried to do this using baloon but it takes very long... Already 24 hours passed and still not finished...
When i tried to search for good ideas in google i found this one:
https://www.erowid.org/archive/rhodium/chemistry/debenzylati...
I already tried this procedure:
A suspension of substrate (10 mmol), ammonium formate (20 mmol), and zinc dust (2 mmol) in methanol (15 mL) was stirred at room temperature, under
nitrogen until the completion of the reaction. After the completion of the reaction (monitored by TLC), the reaction mixture was filtered through
celite pad, washed with solvent and then the combined filtrate and washings were evaporated under vacuum. The residue was taken into chloroform or
ether, washed twice with saturated brine solution and finally with water. The organic layer was dried over anhydrous sodium sulphate, filtered and
evaporation of the organic layer followed by purification either by preparative TLC or by column chromatography.
The yield i got after 5 hours of stirring was ~10%. So seems that this procedure works.
So i wanted to ask, maybe someone already have experience with such deprotection procedure? It looks like something is wrong with the Zinc ammount
used for this procedure (2 mmol)? I think i really need more as in my reaction 1 gr substrate need 100 mg Zinc, sounds to good to be true 
Any good ideas about this procedure?
From reading another topics i started to understand that it's better don't trust to much Indian postings, but in my case seems that it works (only
yield is very poor).
P.S. sorry for my poor English. Also it's my first post in this forum, so please be liberal for amateur chemist
[Edited on 8-5-2014 by ChemistryAddictive]
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Nicodem
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Quote: Originally posted by ChemistryAddictive  | | I wanted to use a Transfer hydrogenation using 5% Pd/C + H2 in 50 C MeOH, but this requires 2 atm pressure, so to do this it's not a good option in a
simple glass flask. |
Well, if you use hydrogen then it is not transfer hydrogenation.
| Quote: | | I tried to do this using baloon but it takes very long... Already 24 hours passed and still not finished... |
Then adapt in the most most logical way, either increase the catalyst loading and/or use 10% Pd-C.
| Quote: | | The yield i got after 5 hours of stirring was ~10%. So seems that this procedure works. |
How did you determine the yield and confirmed that is the N-debenzylation product?
| Quote: | | So i wanted to ask, maybe someone already have experience with such deprotection procedure? |
I doubt that anybody would ever check that procedure as it does not make any sense (even if I ignored the fact that these authors published a number
of known BS articles, all based on the same template).
| Quote: | | Any good ideas about this procedure? |
Forget about it. An Indian article in Synthetic communications is just as suspicious as an Iranian article in Tetrahedron letters.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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ChemistryAddictive
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First of all, thank you for your fast answer.
Well, if you use hydrogen then it is not transfer hydrogenation.
---- Sorry here must be "Catalytic Hydrogenation". To much readings today... I fixed this mistake.
I tried to do this using baloon but it takes very long... Already 24 hours passed and still not finished...
----- Any recomendations for this? At the moment i just have 5 % Pd/C... Now i use 5% by weight to substrate.
Also i have an article for Tranfer hydrogenation, but it using 10% Pd/C and Ammonium Formate, but the problem is as this procedure uses 25% catalyst
by weight to the substrate. And Pd/C isn't cheap...
The yield i got after 5 hours of stirring was ~10%. So seems that this procedure works.
---- I don't have TLC plates at the moment, so i just titrated debenzylated product with HCL and checked the melting point (it can be that i can
lost some product when i done all work-up) Also i checked starting product, it don't react with HCl to make salt. It makes an orange oil instead (I
got three layers when i performed titration: Organic solvent --- Water --- Orange oil. I seperated water layer and evaporated it and got HCl salt of
deprotected amine)
I doubt that anybody would ever check that procedure as it does not make any sense (even if I ignored the fact that these authors published a number
of known BS articles, all based on the same template).
----- But this procedure works and it uses cheap Zn instead of Pd/C But as i
said i think it needs more Zn... As in this procedure they use less Zn than they use Pd/C in this article ( General procedure for selective mono
debenzylation of dibenbenzylamines: The substrate dibenzyl compounds (1 mmol), ammonium formate (3 mmol), 10% Pd/C (100 mg) and methanol (20 mL) were
charged in to a 50 ml reactor. Reaction was stirred for 15- 20 min at room temperature under nitrogen. After completion of the reaction (monitored by
TLC) catalyst was removed by filtration, catalyst was washed with 5ml of methanol. The combined filtrate was concentrated to dryness.... )
Forget about it. An Indian article in Synthetic communications is just as suspicious as an Iranian article in Tetrahedron letters.
---- Really good advice  But it looks so attractive... No pressure, cheap Zn
instead of expensive Pd/C...
[Edited on 8-5-2014 by ChemistryAddictive]
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Nicodem
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I don't know the MW of your substrate, but 5% by weight does not sound enough for an atmospheric pressure N-debenzylation. I would go with at least 10
mol% Pd-C. Even at 5 bar pressure or more, I generally use a couple of mol% Pd-C. Though, the ease of N-debenzylations is quite substrate specific, so
it is a pretty much try-and-optimize issue.
| Quote: | | Also i have an article for Tranfer hydrogenation, but it using 10% Pd/C and Ammonium Formate, but the problem is as this procedure uses 25% catalyst
by weight to the substrate. And Pd/C isn't cheap... |
What can I say? Like I told you, don't be to cheap on palladium. You can try with less catalyst and a longer reaction time. Maybe you will be lucky.
| Quote: | | I don't have TLC plates at the moment, so i just titrated debenzylated product with HCL and checked the melting point (it can be that i can lost some
product when i done all work-up) Also i checked starting product, it don't react with HCL to make salt. It makes an orange oil instead.
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That's not enough to convince me.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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ChemistryAddictive
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I don't know the MW of your substrate, but 5% by weight does not sound enough for an atmospheric pressure N-debenzylation. I would go with at least 10
mol% Pd-C. Even at 5 bar pressure or more, I generally use a couple of mol% Pd-C. Though, the ease of N-debenzylations is quite substrate specific, so
it is a pretty much try-and-optimize issue.
---- If MW means Molecular weight, than my substrate MW is 267 gr/mol. I was adviced to use 5% by weight loading of 5% Pd/C, 2 Atm (~2 Bar) pressure
and 50 C (I was advised by the friend who deprotected this product succesfully in Industrial scale). So seems that this product isn't very complicated
to deprotect As for "try-and-optimize", this why i will try to do it with
ballon, to check the conversation on such pressure.
Also one more interested thing is that this product itself is "N-benzyl protected amine Phopshate salt". And i was advised to use it directly (disolve
in methanol and perform catalytical hydrogenation and only later to basify it to release a "free amine"). Last days i tried to find any information
how this can impact reaction yield and catalyst itself. Any comments about this? But when i done Zinc/Ammonium formate reaction, i first made this
material basic with NaOH.
What can I say? Like I told you, don't be to cheap on palladium. You can try with less catalyst and a longer reaction time. Maybe you will be lucky.
---- thank you for an advice, this is what i am doing right now Only the problem
that i don't have a TLC plates to check the conversation.
That's not enough to convince me.
---- I will send it tommorow to make analysis of this sample. I will write you results But by the all characteristics (physical properties, appearance, smell, MP) it's really deprotected amine HCl.
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Dr.Bob
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N-benzyl amines are always easy to remove in text books. In real life, they can be a nightmare, but if you simply go with more time, maybe a small
amount of acid, then catalytic hydrogenations work well, and are very clean. I have seen people run these for up to 2 weeks, since they are slow,
but they do work, and sometimes time is the best solution if you cannot change the pressure, temp or catalyst.
Transfer hydrogenations would also work, likely better with Pd/C than Zinc, but that may work if given long enough. You could also try Raney Nickel,
and other H sources. All of these may work, but are substrate dependent, which will require some trial and error. Another solution if you want to
repeat this is to use a more labile benzyl group, like 2-chlorobenzyl or others, see Greene for examples. Some of those group are much easier to
remove by Hydrogenation.
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AvBaeyer
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In my experience, N-debenzylations are not a problem if the catalyst (5-10% Pd/C) is of good quality. Also, as pointed out by Dr. Bob,a small amount
of acid, usually a few per cent of acetic acid, can improve the results markedly if one is using an alcohol solvent. Difficult N-debenzylations can be
run in aqueous HCl if the substrate is stable. Using a balloon often works but stirring/mixing of the reaction must be vigorous. In my experience,
poor stirring or agitation of the reaction mixture is usually the reason many balloon reductions fail to work well. In the end, it is best to use a
shaker at 30 - 40 psi hydrogen pressure.
AvB
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ChemistryAddictive
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Dr.Bob and AvBaeyer, thank you for sharing your experience and your advices.
Now i sttired my product for 36 hours, so i am going to check the results. I asked for your help to late, as my sttiring wasn't very vigorous,
becouse i made a mistake when choosed to long magnetic stir bar And if i add to
much Rpm it start to "fly" in a flask
Only good sign is that balloon was shrinking, so i hope that this was an indication that my reaction consumed some H2 and not an indication that it
was leaking I had to add some H2 from time to time. Also i wanted to ask, in
theory this reaction must use 1 mol H2 to 1 mol substrate to deprotect it?
Next question is, as i said in my previous post, my substrate is N-benzyl protected amine phosphate salt. And i use it in this form directly (without
basify, to release the free amine).
So it's still good idea to add Acetic acid?
As for Acetic acid itself, at the moment i have 60%. It's good? Water don't have any influence in such reactions?
My prefered solvent is MeOH, as it dissolves my substrate very well.
Also it's good idea to reuse same MeOH for further hydrogenations?
[Edited on 9-5-2014 by ChemistryAddictive]
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Dr.Bob
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You will need an equal amount of H2 to substrate, but most balloons leak Hydrogen, so in practice you will need a vast excess of hydrogen, but
fortunately, that is cheap. Small amounts of water do not normally bother hydrogenations. I would use ethanol if you can rather than methanol,
solely because it is less prone to fires with Pd catalysts, still possible, but slightly less risk. Good stirring or shaking is a must, as the
hydrogen is not very soluble, and that is the rate limiting factor at low pressures.
A trace (1 or 2 drops normally) of acetic acid or HCl is fine for small reactions, the phosphate salt may be acidic enough to help as well. It does
not have to be much.
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Nicodem
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| Quote: Originally posted by ChemistryAddictive | | Only good sign is that balloon was shrinking, so i hope that this was an indication that my reaction consumed some H2 and not an indication that it
was leaking |
Unfortunatelly, hydrogen readily diffuses trough the balloon and its shrinking is therefore not necessarily an indication of reaction conversion. It
is a positive indication, but it is not conclusive.
| Quote: | | Also i wanted to ask, in theory this reaction must use 1 mol H2 to 1 mol substrate to deprotect it? |
Yes.
| Quote: | | Next question is, as i said in my previous post, my substrate is N-benzyl protected amine phosphate salt. And i use it in this form directly (without
basify, to release the free amine). So it's still good idea to add Acetic acid? |
From the little information that you gave, I assume it is an internal salt, in which case it is already protonated. Also, protonation does not always
help N-debenzylations, though on some substrates it makes a huge difference.
| Quote: | | Also it's good idea to reuse same MeOH for further hydrogenations? |
The only volatile side product is toluene which does not affect much the reaction at low amounts, but can change the solvent properties at higher
compositions. So, if you plan a solvent recovery as part of a production process, you better fractionate to separate the toluene/methanol azeotrope
from the methanol. Even assuming an efficient column, you will loose significant part of methanol after each run due to the unfavourable azeotrope
composition. But who wants to recover a solvent like methanol? It is one of the cheapest (after water), costs less than an EUR per kg.
…there is a human touch of the cultist “believer” in every theorist that he must struggle against as being
unworthy of the scientist. Some of the greatest men of science have publicly repudiated a theory which earlier they hotly defended. In this lies their
scientific temper, not in the scientific defense of the theory. - Weston La Barre (Ghost Dance, 1972)
Read the The ScienceMadness Guidelines!
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ChemistryAddictive
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Hello,
after 32 hours of stirring under baloon, the product was deprotected succesfully
(no starting intermediate recovered). I used 5% by weight Pd/C (50% wet) to starting substrate. So next time i will try to use double of Pd/C and
more vigorious stirring. And try 24 hours...
Also i wanted to ask, maybe you can advice how to reuse Pd/C? Any good procedure? I was adviced just to add 20% fresh Pd/C and use it as it is,
without any washings with acid/or base.
As for methanol:
The only volatile side product is toluene which does not affect much the reaction at low amounts, but can change the solvent properties at higher
compositions. So, if you plan a solvent recovery as part of a production process, you better fractionate to separate the toluene/methanol azeotrope
from the methanol. Even assuming an efficient column, you will loose significant part of methanol after each run due to the unfavourable azeotrope
composition. But who wants to recover a solvent like methanol? It is one of the cheapest (after water), costs less than an EUR per kg.------
I asked this not becouse of the price, but i had to evaporate Methanol in my process, so i was thinking if the Methanol is pure enough to use again -
why not? But you answered to my question. For such cheap solvent i don't going
to do any additional steps to recycle it.
But i still want to try CTH for this deprotection: as i have Ammonium formate, Pd/C and Nitrogen.
I was addviced to use such procedure: 10% by weight 5% Pd/C, 5 eq Ammonium formate and 50 C and stirr overnight.
But all such procedures i can find requires Nitrogen atmpshere. So i think i will do this under Nitrogen. Or this is not necessary?
Also i was advised to use very low ammount of Pd/C comparing to another such procedures. Is longer reaction time will help to use less Pd/C? As in
another procedures, they deprotecting N-benzyl in max 30 minutes (but with huge ammounts of Pd/C, about 30% by weight 10% Pd/C).
Thank you in advance for your answers
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benzoyl
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N-debenzylation options?
I want to deprotect a N-benzyl protected amine, would rather not use pressure reactions or Pd-C.
http://www.sciencemadness.org/talk/viewthread.php?tid=30326
The article discussed in this post (Synth. Commun. 34(10), 1831-1837 (2004)) seems to be controversial, anyone know of other N-debenzylation methods
with inexpensive reagents?
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chemrox
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Li/NH4
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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clearly_not_atara
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Is the amine already protected, or are you planning a synthesis? Maybe use a different protecting group?
Anyway, I found Ce4+, BBr3, SmI2, some weird Ti3+ complex, NaK/silica, and ethyl chloroformate as possibilities (the last two are dangerous)
http://pubs.rsc.org/en/content/articlehtml/2000/cc/b000071j
http://www.tandfonline.com/doi/abs/10.1080/00397919408011190
http://www.sciencedirect.com/science/article/pii/S0040402009...
http://www.tandfonline.com/doi/abs/10.1080/00397919508013417...
http://www.sciencedirect.com/science/article/pii/S0040403909...
http://www.sciencedirect.com/science/article/pii/S0040403904...
Quite frankly if you think any of these looks easier than Pd/C you're insane, though
ceric ammonium nitrate is great if you can buy it.
EDIT: chemrox, I assume you mean hexaamminelithium electride, or tetra(ethylamino)lithium electride, see:
https://www.thevespiary.org/rhodium/Rhodium/Vespiary/talk/fi...
[Edited on 21-4-2016 by clearly_not_atara]
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Nicodem
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Threads Merged
21-4-2016 at 12:27 |
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