I was originally going to post this in the large thread along the same lines, but that thread was all over the place. So, I am using this message to
share a bit of learning about 3,4,5 TMB preparation, the safety inherent in refluxing nitromethane, and a lot of little annoying things about that
"underground' reduction schema from the Rhodium website that were learned the hard way.
Since it has now been quite a number of years since the author's sorority days (back when the girls trying to get in during Pledge Week had to concern
themselves about ill-documented, improvised gray-legal-area matters related to esoteric underground chemistry) please view this as just a series of
non-sequitur rants about this topic that hopefully will help someone out.
There are three sections to this: first, I suggest the best way that one should presumably go about making 3,4,5 trimethoxybenzaldehyde (because who
doesn't need the ability to whip up a batch of the antibiotic Trimethoprim in an emergency situation?) Then I offer my $.02 on the "dangers" of the
Knoevanagel condensation (particularly refluxing the lower paraffins nitroethane and nitromethane.)
Last of all, the "underground' reduction schema that made the rounds in the usual shady places some years ago is certainly worthwhile, but there are a
host of potential "gotchas" in addition to the fact that some of the original documenters of this technique seemed to offer "methodologies" that did
not square with the author's real life experience. So take this as you will, but with nascent middle age looming and "Cialis' figuring much more
prominently in the author's personal life than college-era camping trips and psychedelics, perhaps this will save at least someone a bit of heartache
since it starts to get a little fuzzy after a number of years.
NON-SEQUITUR #1: The feasibility of making 3,4,5 trimethoxybenzaldehyde
First of all, if you are working outside of a professional/university type laboratory setup, it's this author's contention that dimethyl sulfate is
something you should not even mess with at all, even though it's "technically" (cough) easy to make. DMS is some of the nastiest crap around.
What I would recommend is making (or purchasing) syringaldehyde, and then performing a PTC-mediated (specifically tetrabutylammonium bromide)
conversion with dimethyl carbonate in DMF to 3,4,5 TMB. There's a writeup describing just this in the "Prepublication" section here. A FOAF of the
author managed to make a very good stab at this with a good 70% yield; it was proposed that a yield of 90% is not exactly out of the question were
"FOAF" to just up his reflux times/temperatures a real bit such that they were concomitant with DMF's reflux time. Admittedly, dimethyl carbonate and
tetrabutylammonium bromide aren't exactly OTC but the thought of making some toxic crap like methyl iodide or dimethyl sulfate in one's garage gives
me the heebie-jeebies. My *guess* is that a different PTC might substitute as well (maybe the easily acquirable cetrimonium bromide?) However, none
of this is an insurmountable task. (Now, if you've got the ability to do pressure reactoins, well, dimethyl carbonate is simply the way to go
overall, no question about it!)
NON-SEQUITUR #2: The myth of nitromethane "not being safe' to reflux.
Heck, maybe it isn't -- after all, crack isn't exactly "safe" either, but lots of people seem to smoke it without dying, but that being said, I'd be
a bit more concerned about this had I heard even one anecdotal example of how "dangerous" this supposedly is. I've yet to see one concrete example
where a problem was caused by refluxing nitromethane (but then again, I don't hang out with meth cooks that explode their kitchens because they put
acetone in the oven to try out their product or anything like that.) Is refluxing nitromethane 'safe'? OK, maybe we wouldn't want five year olds
doing it, but that said, the Knoevanagel condensation is one of the best, easiest, and most predictable reactions around. I've never heard of one
problem resulting from refluxing nitromethane after literally dozens of Knoevanagel condensations; the ladies dig this reaction since it's
predictable, useful for a whole bunch of stuff, with predictably high yields and textbook-elegant recrystallizations of the final product (dumping the
resulting styrene in ice water and then recrystallizing with methanol doesn't get much more straightforward.) Then again, these Knoevanagel ladies
don't seem to be cranking up the heat to a God-forsaken high temperature (a gentle reflux around or even slightly below the BP of nitromethane is just
dandy for this procedure, as it requires some heat input, but not necessarily a vigorous reflux).
Perhaps some of the danger comes from those "cool guys" that are distilling nitromethane from motor fuel or what have you. If you're too
'streetstyle' &/or unresourceful enough to acquire 99% nitromethane (which is available in at least two or three completely OTC sources, requiring
little more than drying over appropriately sized molecular sieves in order to purify) and have to be the cool guy who distills it from motor fuel or
whatever, take some adequate precautions and purify your product. (This author has found that "Purification of Laboratory Chemicals' is an essential
part of any chemist's bookshelf, so take a minute to look up what you should do with nitromethane and nitroethane.)
If you're really paranoid, if memory serves these Knoevanagel condensations will also run pretty darn well if you just stopper the ingredients and
stick them in a basement somewhere (maybe two or three weeks?) and then just purify the resulting styrenes by boiling in methanol (another winner as
far as nitrostyrene preparation via the Knoevanagel condensation goes as far as this author is concerned: if only all recrystallizations were so
elegant and foolproof.) Talking to the pool guy last week, he told me that his nitromethane reflux fear caused him to prepare these styrenes using
this "Stopper 'n Forget" method, and after 3 weeks he was treated to a pile nice yellow crystals (although they were a bit dirty looking, because the
styrene's gonna degrade a bit, but... if you're really paranoid, etc just do what the pool boy did.)
NON-SEQUITUR #3: That "underground innovation" reduction that made the rounds on Rhodium a while back (cf. http://www.erowid.org/archive/rhodium/chemistry/nitrostyrene...) is very appealnig in that it uses OTC "ingredients" (glacial acetic acid, IPA,
water, aluminum foil, and a pinch of mercury salts) and is procedurally simple. This reaction is actually a good one -- yeah, this works, but it
never was really quite "all that" and the original descriptions of its success simply can't be right on at least a couple of the writeups, with
dangerous consequences if the "instructions" given were followed verbatim. So, if you've become enamored with this method but have not actually tried
it yet, take some time to read what follows.
Yes, this reduction works (don't get too hopeful about getting over a 65% yield) but unless there is some sort of difference implicit in how the
original writeup was describing things, we came to the conclusion after a LOT of frustrating, low yielding trial and error that a the writeups in this
original file were, if not totally wrong, definitely problematic. There could very well be some undocumented "X" factor that caused a discrepancy
between their results and ours: who knows? Perhaps the original writers using grossly different gauges of aluminum foil than we were, perhaps --
because believe me, if you dump 40 g of aluminum into this reaction all at once at the outset as the first writeup on that Rhodium article indicated,
you're going to have a nasty mercury-laden Volcano of Toxicity in your lab in no time short.)
To improve on this method, do this: if you're prepping your aluminum foil using that classic improv coffee grinder method, you do NOT want to add more
than 15 g of aluminum foil to the initial mix, and use a 5L (or larger) flask. After several iterations flailing and failing with this reduction, it
was eventually found that the aluminum foil, substrate, mercury salt(s), and additional GAA/IPA/water solution (which both allows you to flush your
subsequently added substrates and aluminum foil balls down the powder funnel, but also is necessary to account for the large amount of liquid that
will most likely escape through the top of your reflux condenser: if this reaction gets too dry, it turns into an unmovable mass of aluminum and even
a huge stirbar already has problems keeping the reaction mixture stirring correctly.) If you dry this reaction out too much, you'll suffer greatly,
so ensure that it's lubricated throughout the reaction. Aluminum should be added in at slow piecemeal increments throughout the reaction, with 10g of
aluminum being a perfectly reasonable amount to start with with. Adding 90g of aluminum should take about 90 minutes.
(I'll try to lay out all of this in a more streamlined format at the end here, so just bear with me.)
When performing the reduction, set a stopclock, and at regular intervals add the aluminum foil piecemeal (we generally found that 10g aluminum every
10 minutes was a good interval to keep) additional substrate to be reduced, and a little extra GAA/IPA/water to rinse out your addition funnel and to
account for inevitable loss of the reactants, and a proportionate amount of mercury salt to be reduced at regular intervals (again, 10 minute
intervals is usually good, so 90g of aluminum would take you about 90 minutes to add, total.) So, if you're adding 90g of aluminum foil to the
reaction overall, it's recommended you start off with .1 g of mercury salt and 10g of aluminum, 5 g of substrate. During the next iteration, another
.1g mercury salt, a little extra GAA/IPA/water, and a proportional amount of substrate to be reduced every 5 minutes.
(I don't want to overcomplicate this: the only real takeaway here is "add everything incrementally and not all at once.")
Keeping the reacion vessel around 70 degrees Celsius seems to work pretty well; just don't let this run *too* hot. having a couple of ice packs to
cool off your 5L flask throughout the reaction seems to help things as well. Whatever you do, do NOT add the entire gram of mercury salt and more
than (max) 20g of aluminum at the outset of the reaction, unless you want a fountain of toxic mercury sludge shooting all over the place.
Again, in the original writeup, the person purportedly added the following all at once at the outset: 40 of aluminum, an entire gram of mercuric
chloride, and all of the substrate to be reduced at a single time. Apparently he knows something we don't, but this methodology will result in little
but a big toxic mess and an abysmally low yield in our experience.
For the purpose of this little writeup, we are assuming that you wil be using coffee grinder to grind Extra Heavy Duty Reynolds Wrap into "little
globs" for use in the reduction. Place double or triple-folded aluminum foil strips, tear then into 2" or 3" square pieces, and place them in a
Starbucks coffee grinder for about 5 seconds to prepare your aluminum for reduction. The aluminum should be little "globs": not huge thick "globs"
(which will be too thick to reduce during the reduction) and not "dust", which will react too quickly and lead to overly exothermic consequences.
Note that this reduction will run very hot and is kinda freaky, so an extra Graham condenser or the like on top of your reflux condenser can help
prevent wayward GAA from splashing all around your work area. Adequate ventilation is a must since the GAA fumes can be overwhelming so try to get
your logistics in order regarding the addition of additional reactants throughout the course of the reaction: have a "buddy" around who can swap out
the condenser with a powder addition funnel quickly, as you'll want to minimize the amount of time you've got your reaction flask uncovered.
Additionally, prepare a bit extra GAA/IPA/water solution in addition to the molar ratios stated in the initial writeup in order to (a) have something
to flush down your piecemeal-additions of aluminum throughout the reaction, and don't forget to account for the GAA you're adding in addition to the
original amount.
This is important as it was discovered that the final basification process needs the amount of sodium/potassium (KOH being superior) added to exactly
reflect the amount of GAA in there. Now, this is probably not quite true, but if you end up adding not enough because you lost track of all of the
GAA you added you could easily botch the whole reaction. So, simply inventory the total amount of GAA you're adding (both at the outset as well as
the additional amount you need to flush the successive reactants down the powder funnel throughout the reaction) and budget the final amount of KOH
(NaOH also works, but trust me -- just stick to KOH.) you'll need for the final basification process.
Last of all, prepare your final KOH/NaOH basification solution well ahead of time and chill it in the refrigerator. A cool caustic/water blend makes
things go much, much smoother. Don't basify too quickly: add the caustic solution slowly over the course of several minutes.
If this is still unclear, let me break it down to more of a quantifiable schedule:
BEFORE STARTING THE REACTION: Add the entire slated amount of GAA/IPA/H2O, a small amount of mercury salt (.1-.2 g is sufficient), a
small amount of substrate (e.g., 10 grams) and a correspondingly small amount of mercury salt. Ensure you have an adequately sized stir bar in place:
inadequate stirring will greatly lessen your yields and even the biggest/most powerful stir bar will have issues stirring the gray aluminum sludge
you're about to create.
**NOTE** A full gram of mercuric chloride is given as a Procrustean solution for all of these reactions in the original writeup. In practice less can
definitely be used depending on the amount of substrate to be reduced. 20 mmol of substrate probably only requires somewhere between .5 and .75 g of
mercuric chloride.
IMMEDIATLEY AFTER STARTNG THE REACTION: After the initial addition of reactants, we prefer to wait approximately ten minutes before starting the
piecemeal addition of the remaining substrate/reactants/etc. This reaction can get freaky really quickly (it tends to really get freaky around
minutes 20-25.)
ABOUT TEN MINUTES AFTER STARTING THE REACTION: Add another 10g of both aluminum and 5 mmol substrate, another .1 g of mercury salt, a small amount of
GAA/IPA/H2O to wash these down your powder funnel (again, ensure you track how much extra GAA you are adding throughout the course of the reaction)
and then repeat this every five minutes (caveat: around minute 20-30 or so the reaction could be very violent and you might want to wait 7,8 or even
longer between your next addition.)
Repeat this step until all substrate/mercury salt/etc. has been added. If you required 90 g of aluminum, the whole addition process should take you
about 90-100 minutes.
Give this reaction plenty of time to die on its own (overnight is best) and after it cools down a small amount of heat can be applied to the reaction
vessel and stirring recommenced. Let the reaction cool for a while once this has finished.
AFTER THE REACTION: Slowly add your KOH/NaOH caustic water to the reaction (ensuring it has been cooled and you do not add it too quickly. When the
IPA layer containing desired amine reaches the top, tap out the IPA, then *distill the IPA* (don't be fooled into thinking that water-soluble IPA
allows for a shortcut wher eyou just drop the IPA in to a sep funnel to do an A/B extraction since it's water soluble. Distill out the IPA, do your
A/B workup, and then you will, of course, distill the final product with a short path for maximum purity.
[Edited on 25-5-2013 by DH2]
[Edited on 25-5-2013 by DH2]turd - 26-5-2013 at 02:30
Thank you, although this could be a bit more structured and less chatty.
Quote:
What I would recommend is making (or purchasing) syringaldehyde
Buying syringaldehyde to make trimethoxy benzaldehyde seems a little bit irrational, since the latter is wider available and distinctly cheaper. Yes,
it's one more step away from mescaline, but you will not fool anyone - don't buy it together with nitromethane. On the other hand syringaldehyde is of
course much more versatile, opening the road to the nice and benign x-scaline series.
I've posted this a few times before, but it can't harm posting it again: Making syringaldehyde in a Ghetto setting via 5-bromo-vanillin is not
recommended. The 5-bromo and 5-methoxy compounds tend to cocrystallize and therefore cannot be purified by crystallization. Go via syringol.
Quote:
The myth of nitromethane "not being safe' to reflux
Ok, but why bother. There are well documented amine catalyzed condensations in solvent that work good for the 3,4,5-trialkoxybenzaldehydes.
The Al/Hg presented at Rhodium's worked always fine for me. Of course you can't simply scale it up linearly. But see also my recent post in
beginnings: The harsh reaction conditions with AcOH and what not may not even be necessary if you can provide good enough stirring.
