okelly4408
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Help With LAH Reduction Yields
Hi.
For some time now I've been getting quite abysmal yields while working on the very textbook and straightforward reduction of nitrostyrenes using
LiAlH4. The procedure I take is:
1. Suspend the LAH in anhydrous (sold as such and dried further over molecular sieves) THF in the reaction flask under positive N2 pressure and
vigorous overhead stirring
2. Slowly introduce THF solution of nitrostyrene drop-wise
3. Reflux and monitor continuously with TLC
TLC shows the starting material completely consumed and the new spot stains dark purple with ninhydrin indicating the presence of the amine.
The reaction itself is so basic that it is the quench/work-up I fear might be contributing to loss of product in anything. I:
1. Destroy remaining hydride with minimal addition of cold, dry IPA until hydrogen production ceases
2. Transfer thick, gray, sludge like material to a beaker where, with stirring, I add small quantities of 25% NaOH and saturated Rochelle salt
(potassium sodium tartrate) solutions
3. When fine "curds" of aluminum hydroxide develop, I thin with DCM and/or more THF and filter over a pad of celite
4. I wash the cake several times with DCM/THF
However, the aluminum hydroxide "curds" are quite dense and pasty. I worry that the washes are not so penetrating and that product might be staying
trapped within them. Would it be wise to dissolve the whole mass in dilute acid and proceed straight off with an acid/base extraction? Usually after
filtering I strip the THF/DCM under vacuum and THEN proceed with the A/B extraction.
I recover product with yields ranging from 5-45%. Any assistance here or pointers to literature would be really appreciated.
Thank you.
[Edited on 28-7-2025 by okelly4408]
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bnull
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| Quote: | | Any assistance here or pointers to literature would be really appreciated. |
Look up the papers under reference 2 of J. Chem. Soc., Chem. Commun., 1974, 307-308.
You should check here and other pages within the same site. There's a huge wealth of information related to the kind of chemistry you're pursuing and, while not
active anymore (it's an archived copy, mind you), you can surely find something about the substances you're interested in.
Five bucks this will end up in Detritus before the end of the week.
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Niklas
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It won’t be possible to just dissolve it in acid and proceed with the acid base extraction, on basifying, which you‘ll have to do to isolate the
amine, all aluminum hydroxides will just separate again.
However the way you are supposed to use Rochelle’s salt (because how you did it it likely didn’t help at all) is to quench the LAH with a little
water, dissolve in diluted sulfuric acid, then add sodium potassium tartrate (you‘d generally use quite a huge amount, it’s not that well
scalable) and then basify and extract the amine.
In general when washing the aluminum oxide filter cake throughly the yield shouldn’t be lowered either though, it’s best to not just wash it in
the Büchner (don‘t use a frit for that if you don’t hate yourself) but actually resuspend it in some ether or DCM or similar and filter again
(repeat that maybe three times).
With yields as low as 5% I would have serious doubts in the quality of the nitrostyrene though, while LAH reduction is less sensitive in that regard
than borohydride / CuCl2 reduction (which I gotta say is quite a bit nicer with the workup though), it should still be quite decently pure to get a
reasonable yield.
Oh and on an additional note regarding literature, while Shulgin did generally (especially for his later chemistry) just filtered of the oxide
precipitate, there are still a few examples of his older projects outlined in PiHKAL that do follow the proper workup with Rochelle‘s salt I
described above, one example I remember would be TMA-3.
[Edited on 28-7-2025 by Niklas]
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walruslover69
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I have attempted to reduce a nitro styrene years ago and got terrible yields, very similar to what you described. I abandoned the LAH method and used
NiCl2 with sodium borohydride and it worked successfully. It seemed much safer, cheaper and scalable. Not sure if it works on all substrates.
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FableP
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How many equivalents of LAH are you using? Pihkal would suggest that ~5 + eq are required.
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okelly4408
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Hi. Thanks for all of the tips so far. I really appreciate it.
I'll take a look at that paper bnull. And yes, very familiar with the archive. Real trove of information.
I'm not too suspicious of the nitrostyrene in terms of purity, while definitely not analytically pure it seems reasonably so upon TLC inspection and
just by its physical characteristics (melting point/appearance)
When i say I wash the aluminum oxide/hydroxide sludge, I essentially transfer it all back into a beaker and stir vigorously with DCM.
I will check out that entry for TMA-3.
I use 6x equivalent which I was actually suspicious of worsening the yield issue by adding so much pollution. By the end of the reflux, there is still
quite a bit of hydride activity. And that's what has me so confused. As mentioned, I see complete consumption of the starting material and the only
spot left on TLC stains as you'd expect for amine. Sorry to repeat myself but it just is curious.
I'll give the NiCl2 w/ borohydride a try too.
Also, completely besides the point but what is the criteria for going to detritus? I'll try to avoid such posts in the future.
[Edited on 29-7-2025 by okelly4408]
[Edited on 29-7-2025 by okelly4408]
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bnull
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| Quote: | | Also, completely besides the point but what is the criteria for going to detritus? I'll try to avoid such posts in the future. |
In general: posts that have zero redeeming social importance; hardcore spoonfeeding that could have been avoided by opening a chemistry textbook;
outright assholery; presentation of procedures that make no sense or that have been disproved before and yet the person insists they work and then
provides no proof (production of ethyl chloride by filtration of a mixture of ethanol and sodium chloride at room temperature, for example); homemade
nucleosynthesis; discussion of ideas whose sole purpose is to cause harm/death/mutilation for fun or to promote a harmful political/religious ideology
(fabrication of mailbombs and other improvised explosive devices, nerve gases, weapons, poisons); political and religious discussions except where
they affect the relations between chemist and society; ill-planned procedures that are harmful for the operator; attempts to initiate flame wars;
conspiracies based on weak correlations between facts; self-agrandizing or self-promotion as if the person were a better experimental chemist than
Faraday (no one is, but Newton got very close); almost anything written or inspired by PhDChemist and his other sockpuppets; commercialization of
illegal substances or of precursors that only find application in the manufacture of illegal substances or poisons; nonsense (except, sometimes, in
Whimsy); asking for help with stuff at work that the person is being paid to do but is too lazy to think or to do a basic research. There are
occasional exceptions but even then the ScienceMadness Guidelines define what is acceptable in terms of language and content.
In your case, since your interest veers to the psychoactive side of organic chemistry, I'd say the preparation of "boring" substances. "Boring"
substances are those that have been known and synthesized for so long that they present practically no new chemistry. There are literally tons of
papers devoted to them, inside and outside academia. Most of them have become targets of drug agencies and appear in the news with the
police-busts-drug-lab sort of headline: meth, ergotamines, phentanyl. Your "helional to MDMA" post and the "help me extract <psychoactive
principle> from <obviously illegal stuff>" posts that appear a couple of times a year are examples of "boring" substances posts in Detritus.
Edit: This is the kind of chemistry that I don't do but it doesn't mean that I don't read about it.
[Edited on 29-7-2025 by bnull]
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Niklas
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Quote: Originally posted by okelly4408  |
I'm not too suspicious of the nitrostyrene in terms of purity, while definitely not analytically pure it seems reasonably so upon TLC inspection and
just by its physical characteristics (melting point/appearance) |
While I believe that claim, it is however kind of hard to fuck up a LAH reduction so badly to only get a 5% yield when the starting materials were of
reasonable quality, it is a very quite robust reaction and should reliably give around 70-80% yields for nitrostyrenes, and there is no way that so
much got lost in the filter cake even if one wouldn’t wash it at all. And based on the statement that there was still reducing properties on
quenching it can’t really be the LAH.
So either it must have been the nitrostyrene (which catalysts did you use to prepare them btw?) or you fucked up in a different part of the procedure
somehow.
But yeah I‘ll guess you can give borohydride a shot too, either in combination with NiCl2 or CuCl2 (I exclusively use copper but I don’t know if
there is too much of a practical difference). It isn’t as easy of a procedure as LAH reduction (if you want good yields at least, dumping the
styrene into the borohydride solution followed by the copper chloride without any further control will still usually end up in yields of maybe 50-60%,
for some exceptions even higher), but if you take care to first add the nitrostyrene slowly to a cooled solution of brorohydride (you don’t want
excess nitrostyrene present for this initial reduction if the double bond, because otherwise you‘ll make Michael byproducts and such), and only add
the CuCl2 once there is no more orange / yellow color, yields of around 80% are pretty achievable for most substrates after distillation. Another
piece of advice I have is to add the borohydride in portions because some will get destroyed without reacting with the substrate because the solvent
system is partly water, starting with 3,5 eq, adding 3,5 eq after all the styrene is added and 1 more eq once it’s fully discolored and the copper
is added is what I usually do.
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zed
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Umm. This reduction is well documented. But, it is usually performed in Diethyl Ether. So why would you choose to use the more expensive, harder to
obtain... THF?
Yields can be disappointing, but not as disappointing as you are reporting. Yields are dependent upon the type, and location, of the substituents
present on the aromatic ring.
Simply read up on Shulgin's procedures, and utilize his methods. He doesn't always hit the ball out of the park, but his results are generally
respectable.
There is no point in trying to re-invent the wheel. You will have problems enough, just following in the footsteps of the giants of the past.
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okelly4408
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Hi. Just to update this, I switched to Red-Al on bnull's suggestion and immediately began seeing yields in the range of 75-95% depending on the
substrate. This at least proves to me that the nitroalkene is not the problem here. I still want to be able to use LAH and have been running various
experiments in an attempt to pinpoint the exact issue.
One thing I have noticed is that extraction seems problematic. I recently tried a small batch, quenched with dilute H2SO4, added an appropriate amount
of rochelle salt for the amount of LAH used, and then basified until pH > 11. This resulted in a perfectly clear yellow liquid. On extraction with
DCM, I noticed that the yellow color that I normally associated with the freebase amine (and seems quite inseparable from it barring chromatography or
distillation) sticks to the aqueous portion. I took a sample from the DCM extraction and a sample from the aqueous layer, spotted them on a TLC slide,
and stained it with ninhydrin. The DCM shows the characteristic purple of primary amines but the aqueous too produces a reaction (although the exact
color is more on the blue side of things which I attribute to the various mess of salts possibly affecting things).
I am not trying to reinvent the wheel here. THF is an appropriate solvent that can be used in place of Et2O and literature makes this clear (so does
Shulgin in places.) I realize this is allegedly "hard to fuck up" which is what makes it so annoying.
BTW just wanted to add that this is all out of a genuine fascination and love for chemistry. No gain to be had here other than from the satisfaction
in mastering a procedure.
I realize that the amount of tips to be given is somewhat limited as this is a pretty plug and play reaction but just wanted to provide an update
anyway. Really appreciate the help and replies
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Bubbles
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What is the procedure you used for the Red-Al reduction?
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bnull
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| Quote: | | What is the procedure you used for the Red-Al reduction? |
One of these:
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stephill92
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I'm sure you've already looked into this but have you tried using the Fieser workup?
https://www.chem.rochester.edu/notvoodoo/pages/magic_formula...
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