08-25-04 14:49
No 527262
After reading rhodium's page, some things sounded too easy.
Getting woodrose seeds,grinding, defatting them, extracting with ethanol and purifying either by recrystallization or chromatography to pure LSA, dumping them in some KOH soln to hydrolyse to lysergic acid, making some diethylamine from DEET + NaOH and coupling the diethylamine and lysergic acid with some BOP reagent (or PyBOP since this is non-toxic) or HATU or some other coupling reagent to yeild LSD. Since the only reaction is the BOP reaction and these are touted to yeild high in room temperature in a couple of hours, the yeild should be immensely higher than the old-style multiple-rxn synthesis's.
Why does this seem -too- easy? What's the catch? Everything is OTC, and PyBOP doesnt have any suspicion around it.
It's too easy..
(Hive Bee)
08-25-04 17:33
No 527274
I guess the problem lies somewhere in those lines:
extracting with ethanol and purifying either by recrystallization or chromatography to pure LSA, dumping them in some KOH soln to hydrolyse to lysergic acid, making some diethylamine from DEET + NaOH
purifying LSA from plant matter is a bitch to work with unless you use column (or other) chromatography; KOH hydrolysis has to be done carefully (as you know, LSA isn't that stable), then there's the isomerisation/rotation question, and I don't know about making diethylamine from DEET (what's that?), maybe it is easy to perform, maybe not.
The coupling reaction sounds good though, but then again: where to obtain the coupling reagent from? Synthing your own isn't that easy either (peptide chemistry is a chapter in itself).
My personal favorite is the reaction described here (Post 412547 (pHarmacist: "Synthesis of LSD from Lysergic Acid", Tryptamine Chemistry), as it starts with (optically pure) lysergic acid too (pretty simple: defat/extract woodrose seeds, chromatograph and isolate optically active isomers via tartrate), and promises acceptable yields with using easy chemicals (DMF, diethylamine and CDI and obviously that gas cylinder of argon/helium/N2 or whatever) and affordable equipment. Only thing that could bee difficult is getting hold of some carbonyldiimidazole. Doesn't sound very common!? (any ideas for synthing your own?)
Seems like the problem with those -too- easy looking LSD synths is obtaining the needed catalysts/coupling reagents IMO.
Greetz A
Pleased to meet you hope you get my name.
But whats puzzlin you is the nature of my game!
(Hive Bee)
08-25-04 23:16
No 527324
It's true that these coupling reagents are not very common. However, the plus side is most of them ought to be, I think, unsuspicious to purchase, and could likely be obtained through a smaller chemical house. Amide formation using reagents like DCC or EDC (1-[3-(Dimethylamino)propyl]-3-ethylcarb
It seems to me that with lysergic acid however, intermolecular reactions between one's carboxylic acid and the other's indole amine might be a problem. How does the reactivity of the indole amine compare to the reactivity of diethylamine?
Anyway, I think something like EDC might work better then an activating agent like HBTU, at least in ease of post-reaction purification. The first wall to get by though really is if one could hydrolyze the LSA's amide easily without blowing it all to hell.
-SpicyBrown
(Hive Bee)
08-26-04 08:23
No 527437
Getting the coupling reagent is not a problem in this case.
purifying LSA from plant matter is a bitch to work with unless you use column (or other) chromatography
Of course, but we're talking two chromatographs per the entire synthesis for a product which makes it worth it. If someone was too lazy to not purify thier product/precursors then they shouldn't be messing around with this kind of stuff.
KOH hydrolysis has to be done carefully (as you know, LSA isn't that stable)
LSA hydrolysis information was taken off Rhodium's page.
"Lysergic Acid From Ergot Alkaloids.
Dissolve 20 g of the alkaloid (use any of the above or one of its isomers or a combination) in 200 ml of 1 M methanolic KOH solution (this is made by dissolving 14 g of KOH in 250 ml of dry methanol) in a 1 1iter evaporation flask (heavy walled construction). Evaporate the methanol off. Add 400 ml of 8% aqueous (water) KOH solution to the residue and boil for one hour under a slow stream of nitrogen that is allowed to flow through a small orifice for exhausting purposes. Cool, acidify with dilute sulfuric acid, and shake in a separatory funnel with 1 1iter of dry ether. Separate the lower aqueous layer and filter it with vacuum assist. Wash the precipitate with 20 ml of dilute sulfuric acid. This is lysergic acid; store as described later in this chapter."
It sounds like someone's already done this..
then there's the isomerisation/rotation question
Seperation: Precipitate the iso-lysergic acid by adding some 10% HNO3, filter, add more portions until no more precipitate forms. Convert it to lysergic acid by adding 3 ml of 10% KOH per every 0.1 g of iso-lysergic acid, heat on steam bath for 1 hour under a nitrogen atmosphere. Precipitate the changed lysergic acid by acidifying with glacial acetic acid.
The only annoying thing in that is the steam bath/nitrogen atmosphere, but still, it gets your iso-lysergic acid to lysergic acid.
I don't know about making diethylamine from DEET (what's that?), maybe it is easy to perform, maybe not.
Post 447646 (Rhodium: "DEET -> Diethylamine", Newbee Forum)
The coupling reaction sounds good though, but then again: where to obtain the coupling reagent from? Synthing your own isn't that easy either (peptide chemistry is a chapter in itself).
That's covered. They can be bought without suspicioun, one needs to spend only 10 minutes to find a suitable supplier for peptide couplers who mail worldwide. Those who seek shall find. PyBOP is easiest to get around here, so one would assume this would be used however SWIM's friend touted using a relatively new coupler designed for coupling dialkyl groups or, meaning a higher yeild, since it's coupling with an dialkylamine.
In regards to using CDI, read this post.
Post 458213 (PapaSmerck: "flipper yield discrepancies", Tryptamine Chemistry)
Because of it's byproduct to CO2, basic spikes will probably lower yeilds. SWIM thinks HCTU is a better option. This performed better on tests then BOP/PyBOP, with less racemization which I believe is something we can do without.
Contstructive critisim please!
(Hive Bee)
08-26-04 08:47
No 527439
SpicyBrown:
How does the reactivity of the indole amine compare to the reactivity of diethylamine?
It is by far the weaker base. As long as there is excess diethylamine, the indolic NH2 won't react to any appreciable rate (or did I miss something?)
n00dle:
Ok, so it seems the coupling reagent wouldn't be a big problem, provided one has a rotovap and inert gas setup; this peptide coupling thing sounds more and more interesting to me (especially as I like "toss in and stir for x hours"-reactions very much
) - but a problem which arises no matter if CDI, BOP, pyBOP or others are used: how much woodrose seeds would one bee have to extract to get sufficient (lets say 1g) precursor after thorough purification? Multiple kilos? How to obtain such quantities (ok one could buy it - expensive)? And 50 gallons of solvent? (but I agree with you: the product justifies every work and hassle, as long as you don't deal with a serious health hazard like phosgene or cyanogen bromide)Greetz A
Pleased to meet you hope you get my name.
But whats puzzlin you is the nature of my game!
(Hive Bee)
08-26-04 10:03
No 527450
provided one has a rotovap and inert gas setup
Inert gas setup: argon/nitrogen tank, im sure these can be got from welding, regulators, just make friends with a welder and all your problems are solved. Into a 2-holed stopper in a flask place some glass tubing extending down to the bottom of the flask, and in the other hole, a bit of tube and connect it to a very VERY weak valve so you dont overpressurise enough to blow the vessel. Im talking like, even a water airlock would be sufficient. Charge the vessel with your solvents and chemicals, and very slowly regulate some inert gas through the solvent/chemical solution and up into the flask. This will create positive pressure blowing the air out of the flask, and also by bubbling it through the solution (argon/nitrogen won't react easily at all) you will remove any dissolved oxygen/Co2. After you've flushed the flask (do an oxygen/co2 test at the end of the water-airlock) turn off the gas and leave it connected. Voila, one reaction vessle with no air in it.
A rotovap would be handy, but shouldnt really be necessary, if one chooses the right solvents simply evaporating under vaccum should be fine. But if one insists, there is a ghetto-prep for a rotovap on Rhodium's site.
But a problem which arises no matter if CDI, BOP, pyBOP or others are used: how much woodrose seeds would one bee have to extract to get sufficient (lets say 1g) precursor after thorough purification?
Again on Rhodiums page, 200grams of woodrose seeds would provide roughly 1 gram of LSA which upon hydrolysis using NaOH or KOH 0.5gm of usable lysergic acid. But, SWIM just read about using tetrabutylammonium hydroxide at 30C for 20 hrs to yeild 80% with less than 3% of iso. Figuratively speaking, at less than 3% iso, a person may not even choose to seperate that isomer as it won't do anything anyways, and it's in such small quantity (keep in mind, purity is your god).
200gm of seeds is easy to come by. Even taking say 20 seeds and planting them out, in 2 years you'd have a sustainable source of woodrose seeds. SWIM's friend's 2 year old plant covers a whole side of his house, and regular pods have 4 seeds in them. Plus, they seed twice a year, so one could take multiple harvests and place the seeds into a vaccum bag and suck all the air out, keeping it in a dry dark place should preserve them from degredation until enough seeds can be aquired.
[/blue]And 50 gallons of solvent?
For 200gm seeds, 1liter of nonpolar and 1liter of slightlypolar solvent were used. I think 2L of solvent is jusitified for a person's private lifetime amount of 'cid.
[blue]but I agree with you: the product justifies every work and hassle, as long as you don't deal with a serious health hazard
woodrose seeds --> toluene defat --> A/B extract to Lysergic Acid tartarate --> dump in some tetrabutylammonium hydroxide (exotic yes, but worth it, shouldn't be watched) to get 80% usable lysergic acid with a trace of iso-lsd, removed by changing PH and filtering, then reverting to original PH. DEET bug repellent can be bought anywhere, dump that into 10% NaOH re:rhodium's post and distill into hcl, boill off the water to get diethylamine. Dump 1eqmol lysergic acid into 1.05 eqmol PyBOP reagent and 2 eqmol diethylamine, keep it stirring for 3 hours, remove the lsd with a solvent, and chromatograph as freebase or tartarate salt.
Nothing here is really toxic or that dangerous, and because you only really need one chromatograph at the end (presuming you defatted the seeds like a mofo and you acid/base extracted correctly), so almost all of this can be done in the dark or with minimal light and therefore could be done in a day easily. Prepare everything beforehand, and even if you have to bring it into the light for 10 seconds to see what you're doing, big deal, no massive degredation.
(Hive Bee)
08-26-04 16:39
No 527493
It is by far the weaker base. As long as there is excess diethylamine, the indolic NH2 won't react to any appreciable rate (or did I miss something?)
That's what I thought, just wasn't 100% sure. Thanks. Guess that takes care of that portion.
n00dle, that's excellent regarding the amide hydrolysis. With respect to the procedure involving tetrabutylammonium hydroxide - if it is indeed a far superior route, a preliminary SciFinder search seems to indicate that quarternary ammonium hydroxides can be made from their corresponding iodides using silver oxide in water. Around here, tetrabutylammonium iodide is extremely common.
As to the coupling agents, do you (n00dle) have any idea what this new coupler suited for dialkyl groups is? Would be worth looking into. These coupling reactions are nice and fast as well, in solid-phase peptide synthesis someone I once knew used HBTU as the coupling agent, allowing each amino acid to react with the HBTU (DMF as solvent) for 2 minutes prior to addition to the peptide resin, where it was allowed to run for 5 minutes before flushing the reactants away; this minimized racemization and gave high coupled yields in under 10 minutes, which is pretty cool if you think about it. Never used HBTU for solution-phase coupling however; both EDC for normal amide formation and 1-hydroxy-7-azabenzotriazole (HOAt) for dipeptide linkage have been personally observed by my previous friend to produce exceptionally high yields.
The inert gas setup is indeed a breeze; by bargain-hunting, someone put together a setup with a small tank and regulator for under $100, the argon fill was around $15. This is all in the name of welding.
I really think this seems like a worthwhile idea, even worth running two columns for purity's sake.
-SpicyBrown
(Hive Bee)
08-27-04 03:40
No 527639
Even taking say 20 seeds and planting them out, in 2 years you'd have a sustainable source of woodrose seeds. SWIM's friend's 2 year old plant covers a whole side of his house, and regular pods have 4 seeds in them. Plus, they seed twice a year
I'm a chemist, no flower grower
! And they're harder to harvest than wine (manually of course) - 50 seeds usually amount to 6 grams, so harvesting would take a bit of time even if 4 seeds can be collected at once 
. But they can also be bought, that's true - and if they indeed contain 0.5% lysergic alkaloids, it is not that expensive anymore. Man, you're lucky! Where SWIA lives, HBWR don't become that old (too cold here), and most surely they don't become 2-yeared, cover whole houses and seed twice per year! Wish I lived where you do (is it maui/hawaii? *lol*)... (SWIA is green with envy )So to return to your original question: what is difficult about making acid? The only possible problems I could think of can easily be circumvented, as you both pointed out. So I myself begin to wonder about the simplicity of using peptide coupling agents, and why it hasn't gained much more popularity!?
(oh, don't forget to use brown glassware or wrap your clear glassware with aluminum foil or similar; lysergic compounds aren't that light sensitive as you might think; better be on the safe side though.
But still: the lighting problem/hype cannot really be the reason for the lack of poluparity with these rxns IMHO!)
A
Pleased to meet you hope you get my name.
But whats puzzlin you is the nature of my game!
(Hive Bee)
08-27-04 08:58
No 527743
It'll be a few days before I find out what the dialkyl coupler was. Anyhow, out of the whole method SWIM understands the individual couplers the least, so if someone could suggest a good standard coupler that'd be cool. EDC was mentioned, what were the yeilds on coupling with EDC?
(Hive Adickt)
08-27-04 11:07
No 527750
Iff you know your chemistrye acid is not hard to make.
The big problem is obtaining the lyserg acid (or some kind of ergotamine).
Personal I would make it with peptidecouplings, but the shulgin way is also fine.
(Hive Bee)
08-27-04 14:56
No 527773
Iff you know your chemistrye acid is not hard to make.
..redundant statement.
The big problem is obtaining the lyserg acid
This was already addressed in the thread. The starting material is not in question. Surely you noticed that when you clicked on the thread called 'LSD VS peptide coupling...'
(or some kind of ergotamine) There are different kinds of the same chemical?
Personal I would make it with peptidecouplings, but the shulgin way is also fine.
Sigh.. Please post things that are relevant to the topic, nothing in your statement actually helped any of us out, it ws merely some form of discussion, and discussions belong in 'The couch' forums. Please redirect statements like your last post there
(Hive Bee)
08-27-04 18:07
No 527798
At least we know that respectable Hest would opt for peptide coupling, too
!But true is that the precursor problem is not an issue of this thread anymore.
Sure, the shulgin way is well-explored - but not as nice to work with as BOP/HBTU/DCC (is CDI normally used in the same fashion like these; for coupling amino acids?) from what I can see.
Which peptide coupling reagent would you suggest Hest? And why?
A
Pleased to meet you hope you get my name.
But whats puzzlin you is the nature of my game!
(Hive Bee)
08-27-04 18:57
No 527803
Personally SWIM thinks with the almost shockingly good yeilds from peptide couplers, It doesn't really matter at this stage. People jizz thier pants if they used the old method and got 20% yeild. With even standard peptide couplers like BOP, coupling a carboxylic acid with an amine as shown on Rhodium's page got a whopping 98% yeild. SWIM thinks for now, BOP is the way to go. SWIM just needs someone educated to say that yes, BOP + lysergic acid + diethylamine will yeild a signifigant portion of lysergic acid diethylamide. (since all the peptide rxns yeilded in like, the high 80% range or more.)
(Hive Addict)
08-27-04 19:10
No 527807
Did you see this: Post 353379 (Rhodium: "New LSD analogs from the Nichols Lab", Tryptamine Chemistry)?
fear fear hate hate
(Hive Bee)
08-27-04 19:48
No 527812
...this means the following:
pyBOP reacts with the acid to give an acyloxyphosphonium salt and the amine reacts with this intermediate to give the end product.
As a side note, pyBOP is used in place of BOP, since BOP yields the carcinogenic HMPT as a side product.
Those phosphonium coupling reagentia give better yields than DCC (dicyclohexylcarbodiimide).
(Post 355652 (Cyrax: "Nice, they use the pyBOP coupling reagent, which ...", Tryptamine Chemistry)
- seems like it was good to know that before beginning to choose one's coupling reagent!?
And one thing I don't get: in the original Nichols paper Rhodium references to, they use 2,4-dimethylazetidine (secondary amine, too) instead of diethylamine - but what's the role of diisopropyl-ethylamine (tertiary amine)? Is it used to act like a buffering agent? (for buffering what?)
Synthesis of Lysergamides (general method)
Lysergic acid monohydrate (200mg, 0.75mmol), pyBOP (426mg, 0.82mmol), and the appropriate 2,4-dimethylazetidine (109mg, 0.9mmol; replace this with equimolar amount NH(Et)2 to yield lysergic acid diethylamine) were suspended in 20ml of CH2Cl2. Diisopropylethylamine (193mg, 1.5mmol) was added, and the reaction was stirred for 3h. The reaction was then quenched by the addition of 20ml of 0.75 M concentrated NH4OH. The CH2Cl2 layer was separated, and the aequous phase was extracted with 10ml of CH2Cl2. The organic layers were combined and washed with H2O (2x 30ml) and brine (15ml) and dried (MgSO4). Filtration and solvent removal by rotary evaporation under reduced lighting, followed by drying under high vacuum, produced a light golden foam. This crude product was then subjected to purification(..)
..sounds indeed really easy! But why the tertiary amine?
Greetz A
Pleased to meet you hope you get my name.
But whats puzzlin you is the nature of my game!
(Hive Bee)
08-28-04 06:08
No 527885
YES!!! Thank you SO MUCH for that post. Now we know it works!!! :D :D :D :D
On the sidenote, a total guess, that maybe they add a higher boiling amine to the lower boiling amine that is used to couple, so that the solutions BP is raised. People have had issues trying to couple with some amines that have BP's of 3 degrees celcius. But then you'd wonder, you'd probably get a mixture of coupled lysergic acid amines. Hmm. Either way, as proof of the methods on Rhodium's site, a 'supporting' amine is not required. FANTASTIC! This is excellent news.
(Off Rhodium's page)
Coupling with BOP-Reagent
Example:
A solution of tert-butyloxycarbonyl threonine (2.19g, 10mmol) (the carboxylic acid) and phenylalanine methyl ester hydrochloride (2.16g, 10mmol) (amine hydrochloride) in 150mL ACN is stirred at RT while the BOP-reagent (4.42g, 10mmol) is added, followed by the addition of triethylamine (2.2g, 2.8mL, 20mmol). The rxn is stirred at RT for 1.5hr. 100mL of a saturated NaCl solution is added and the product extracted with EtOAc 3x. The combined organics are washed with 2N HCl, H2O, 5% NaHCO3, and then H2O. The organics are dried over MgSO4, filtered, and concentrated in vacuo to give the dipeptide (3.74g, 98%).
Here they even use the hydrochloride salt of the amine! This helps us also as it is easier to work with diethylamine hydrochloride than diethylamine itself.
WEEEEEEEEEEEE :D
(Hive Bee)
08-28-04 06:54
No 527896
Diethylamine is a liquid, bp around 55°C if I remember correctly. So it isn't that hard to handle.
And I just wanted to point out that the synthesis I retyped originates from ../rhodium/pdf /azetidine-lsd
..but I mainly retyped it for getting quicker help with my problem - understanding the role of tertiary amines in this coupling reaction! triethylamine (2.2g, 2.8mL, 20mmol) is used in the general peptide synthesis on Rhod's page you posted here, again there is some tertiary amine present, and I'm not very content until knowing about the purpose of doing so - although the fact that this synth seems to work nicely for making lysergamides is indeed already good to know, just for educayshunnal purrposess
..(oh, and about But then you'd wonder, you'd probably get a mixture of coupled lysergic acid amines. Hmm. Either way, as proof of the methods on Rhodium's site, a 'supporting' amine is not required. React carboxylic acid with a tertiary amine? How would that work? But anyway, it was just your guess... and I guess you meant the sketchy, old doc on Rhod's site suggesting the use of peptide coupling reagents, not the general peptide coupling reaction with BOP you posted? 'Cuz the procedure in your post uses tertiary amine too, so I would say it is needed with these rxns for some reason?!)
(hey wait! I think I even know a biologist doing lab work regularly, and HIS SPECIALTY ARE AMINO ACIDS
- maybe I will ask him about the topic, surely would be interesting to learn about from someone with experience in the field... ) Greetz A
my OTC idea involves several liters lsyergic acid, plutonium and 2 tons of wheat starch!
(Hive Bee)
08-28-04 10:46
No 527930
A,
Yeah, I was shooting shit in the wind about that last statement. However just because a tertiary amine is required doesnt meant one has to understand why! ( althought it'd be nice to know :D ) Perhaps it's used to stop some sort of side reaction or something. But procuring some triethylamine or a tertary amine might be a bit more tricky. Any ideas for this?
(Hive Bee)
08-28-04 18:41
No 527972
just because a tertiary amine is required doesnt meant one has to understand why! ( althought it'd be nice to know :D )
Exactly - personally, I would rather try to fully understand the reaction before experimenting with ergot precursors from seeds - simply too much work involved in its isolation, therefore I wouldn't want to fuck up any of it because of my own stupidity - better learn about it before doing it).
After having done the incredible and UTFSEing for tertiary amine
- some tertiary amine syntheses:Post 488687 (Organikum: "Mono and trimethylamine by electrolysis", Novel Discourse)
Post 374511 (terbium: "No gas is evolved.", Chemistry Discourse)
Post 450362 (Chimimanie: "Maybee", Tryptamine Chemistry)
...and maybe here lies the answer to my question about tertiary amines, too: Post 400250 (Vibrating_Lights: "Missing part", Tryptamine Chemistry)
- May I cite Vibrating_Lights:
"The amidization is run in DCM. 3eq of trimethylamine is added dissolved into the DCM then the Lysergic is added followed by the thionyl Chloride then the Diethylamine. the triethylamine is there to imediatly soak up the HCL as it is formed. otherwise the HCl is going to harm the molocule. The triethylamine is too large of a molocule to add to the Lysergic acid chloride so that is not a concern. Following the rxn the sulution is concentrated in vaccume and is taken up in Alcoholic NH3. This is extracted in ethylacetate and run through a cromotography collum."
and further, about the question if different tertiary amines can be substituted:
"either will work. and yes it can be used with the POcl5 synth. Honestly though if you can get get POCl5 then you can probbly get DCC&HBTU. The DCC route is much cleaner i hear. A good friend routinuely uses dcc&Hbtu in the coupling of amino acids and highly recommends it over any of the other coupling techniques. It is good pratice too when working with LA hydrate to induce the LA into the rxn vessel dissolved in DCM and pass it through a silica drying tube to dry it. these silica tubes should be used in introducing any reactants. this will also keep moisture from the atmosphere from entering. Back to the DCC it is very mild and very fast. with that synth basicly one would just add reactants and in 30 mins it is done and yeilds over 80% with little or no iso-lsd produced. There are refs for all these procedures."
Hmm.. VL: If you read this, would you care to answer my little question? (why is tertiary amine used) and maybe tell us a bit about the use of DCC? That would be nice, too..
...anbd suddenly, the next question arises
: which solvent to use? Anhydrous conditions, introducing reactands through silica column - or dumping them just into de-ionized ice-water? (I never heard about water being used as solvent for makin 'cid, that's why I'm unsure about this!) Guess it strongly depends on which coupling reagent is used, no?And, update about required equipment: BIG soxhlet xtractor & condenser! (for seed extraction
)Greetz, A
Pleased to meet you hope you get my name.
But whats puzzlin you is the nature of my game!