Author Topic: LSD vs peptide coupling  (Read 14278 times)

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  • Guest
« Reply #40 on: August 31, 2004, 01:25:00 PM »
Usual the nature produce only one isomer, so it would not bee a suprice to mee if the Woodrose did that as well.

From the fermentation of Claviceps you only get's the right isomer (usual you get's all kind's of ergo..wathewerer), but after the hydrolyse you have the right isomer of the accid.
PErsonal I think this is the easyest way to 1g of the acid, but that is another (alredy cowered)

Post 519261

(Bubbleplate: "Process for Isolation of Indole Alkaloids", Tryptamine Chemistry)


  • Guest
Since the LSA in woodrose is active, it's the...
« Reply #41 on: September 01, 2004, 11:42:00 AM »
Since the LSA in woodrose is active, it's the right optics anyhow. I really doubt woodrose produces mixtures of d,l lysergic acid amide..

Unless of course hydrolysis step yeilds different optical isomers. If it doesnt, then there's nothing to worry about.

Plus even if one doesnt seperate any theoretical optical isomers or even isomers, the amounts should be so small and won't use up any signifigant amount of coupling reagent. Plus, forming the tartarate salt at the end and chromatographing should leave both iso-lsd and the useless optical isomer behind, no?

In regards to extracting them, why can't we reuse the solvent by means of acid/base extraction? Or maybe a ghetto watercooled soxhlet with a low BP solvent would help.


  • Guest
vacuum soxhlet
« Reply #42 on: September 01, 2004, 05:19:00 PM »
forming the tartarate salt at the end and chromatographing should leave both iso-lsd and the useless optical isomer behind, no?

Chromatography separates iso- from normal, but not d- from l-lysergic acid diethylamide. But fractional crystallization via l-tatrate gives optically pure products (d-/l-..)
I just thought that using a racemic mixture of d/l-lysergic in the coupling step would mean a racemic end product - and this would mean half of the coupling reagent got used up forming the unwanted l-lysergic acid DEA ( :) ), therefore it might bee advantageous to separate d- and l- before coupling it with the secondary amine.

But I just thought about ephedra: this plant produces only one optical isomer, too - chances are good that HBWR will do, too... :-[

What's ghetto about soxhlet with methanol?  :)  The soxhlet apparatus would have to be water-cooled anyway (better said the condenser it is equipped with), and when slight vacuum is applied, the necessary heavy reflux can be had at slightly above room temp. - doubt that this will destroy any LSA, as the temp. of the boiling solvent would be <50°C (depending on vacuum strength)...
(and LSA is not as fragile as LSD-25)

greetz A


  • Guest
puzzled by rotation
« Reply #43 on: September 01, 2004, 05:42:00 PM »
In my last post, I said: "Chromatography separates iso- from normal, but not d- from l-lysergic acid diethylamide. But fractional crystallization via l-tatrate gives optically pure products (d-/l-..)". But after having read this thread again, I'm very unsure about the chromatography thing:

The residue was purXed and fractionated by radial centrifugal
chromatography (Chromatotron, Harrison Research) using a silica
gel rotor and eluting with ethyl acetate in an N2-ammonia atmosphere.
TLC (silica gel, EtOAeNH3) showed a large blue
fluorescent product spot at R, 0.21 corresponding to the (R)-2-
butyllprgamide and a much smaller spot at Rf 0.15 corresponding
to the S isomer. The faster moving component was collected and
concentrated by rotary evaporation
(they separate R/S isomers)

Ehmmm... - now I'm very puzzled: they separate R/S via chromatography?? I thought R/S was the same like d/l, whereas the iso/normal orientation was molecular, not optical?  :-[

Strange, especially when seen in connection with the following (taken from other paper):

"As the chromatogram is developed with the same solvent, two blue fluroescing zones appear on the alumina column. The more rapidly moving zone is d-lysergic acid N,N-diethylamide" (...) "The di-iso-lysergic acid N,N-diethyl amide which remains absorbed on the alumia column as the second fluroescent zone is removed from the column by elution with chloroform. The "iso" form of the amide is recovered by evaporating the chloroform eluate to dryness in vacuo." (they separate iso- from normal LSD)

Now what does column chromatography do exactly? separating iso from normal, d- from l- (or R- from S-), both..?

(Help! I can't believe that noone of the >500 bees having already visited this thread does know an answer to this!?)

Greetz, A


  • Guest
« Reply #44 on: September 01, 2004, 09:13:00 PM »
Take care when talking stereochemistry

There are two types of  steric compounds
Isomers that are mirror images of each other are caled enantiomers, just like d and l amphetamine. They have only one chiral carbon atom.They are both chirale and have identical properties in an symmetrical (non chirale) enviroment, that mean the same meltingpoint ect.
This mean that they are imposible to separate on a standard TLC plate, iff you want to separate them you need an chiral TLC plate.
The next type are diastereomers these molecules have more than one optical carbon and have different chemical propertiesthat means different meltingpoints ect and, you can seperate them on TLC plates.
So you can separate your mixture of four types of lysergacid into two mixtures of racemic mixtures.
So to anser the quistion we have to know witch type you want to separate.
The short anser is that they separate iso from the fun stuff. They start wit the right isomer of lyserg acid (as you will doo)


  • Guest
Chlorine vs. Chloride
« Reply #45 on: September 01, 2004, 09:23:00 PM »
I Think that Shulgin has a good point here. The big LSD-killer is not light but chlorine ions.

Hest: I assume that you are not talking about chloride ions here, but rather free chlorine and any charged species formed by its aqueous dissolution? I don't think chlorine can be formed to any great extent by UV irradiation of aqueous chloride solutions, or the ocean surface would be sterile.


  • Guest
Thanks! (finally)
« Reply #46 on: September 01, 2004, 09:46:00 PM »
Chlorine from tap water maybe? (I know someone who ruined a big bottle of liquid by diluting it with tap water  ::) , that's why I mention it)

About the stereoisomers: So there are d-isolysergic, l-isolysergic, d-lysergic and l-lysergic.
What we want is every "d-" form, so assuming that HBWR don't contain only d-LSA but also l-LSA (I still don't believe plant alkaloids are optically pure  :) ), tartrate salt formation via l-tartaric would be in order first (and maybe some l-(iso)-lysergic would have to be discarded - or can it be converted to something useful?), followed by separation of "iso" from "normal" (by column chromatography or via pH adjustment/extraction) then isomerization of d-iso-lys. into d-lysergic (or use the LSA->lysergic hydrolysis method suggested by nOOdle, since it produces nearly no iso), and then one would have pure d-lysergic acid diethylamide with very little iso contamination, upon pyBOP coupling w/(Et)2NH, right?

(always assuming the LSA->lysergic acid hydrolysis step would give a racemic mixture of all four diastereomers)

BTW Thanks a lot for clarifying on that!  8)

Greetz A


  • Guest
forget my last post
« Reply #47 on: September 01, 2004, 10:12:00 PM »
Just realized that I already suggested a procedure that results in pure d-lysergic acid earlier in this thread:

Aquire seeds, crush, dry in dessicator (or similar). Defat by extracting thoroughly with nonpolar (preferably low-boiling, like DCM), remove solvent traces with vacuum, extract *very* thoroughly with lots of dry methanol (maybe using vacuum soxhlet), concentrate in vacuo, then column chromatograph and maybe a/b to isolate LSA, hydrolyze LSA to lysergic acid (KOH).

Separate iso- from lsyergic (HNO3) and isomerize with KOH. Combine the two  portions of "normal" (non-iso) lysergic acid, and separate optically pure d-lysergic acid via tartrate. Store cold/dark and under inert gas.

Make diethylamine from DEET bug repellant. (make sure you have very good purity here, too)

Make trimethylamine with one of the known methods (I would go for paraform/NH4Cl/160°C, but that's just me) or aquire any other tertiary amine - Purify *very* thorougly...

Turn off the light - illuminate your lab with candles...

...should do quite well! (only correction: first a/b on plant extract, then column chromatography)  :)

Greetz A


  • Guest
could you elaborate abit on the use of ...
« Reply #48 on: September 02, 2004, 02:12:00 PM »
could you elaborate abit on the use of l-tartaric acid to isolate optically pure lysergic acid? why use l- over d- ? I searched the FSE and couldnt find it.


  • Guest
I searched and found..
« Reply #49 on: September 02, 2004, 04:31:00 PM »
You are supposed to use d-tartaric acid to get d-LSD...

From "Merck Index":

"D-Tartaric acid: (2S,3S)-2,3-Dihydroxybutanedioic acid

(unusual tartaric acid;  unnatural tartaric acid;  l-tartaric acid;  (-)-tartaric acid;  levotartaric acid;  D-threo-2,3-dihydroxysuccinic acid)

Levorotatory tartaric acid having a dextro configuration.

(2R,3R)-2,3-Dihydroxybutanedioic acid

(ordinary tartaric acid;  natural tartaric acid;  d-tartaric acid;  (+)-tartaric acid;  dextrotartaric acid;  L-2,3-dihydroxybutanedioic acid;  d-a,b-dihydroxysuccinic acid;  Weinsäure (German);  Weinsteinsäure (German))

Dextrorotatory tartaric acid having a levo configuration."

About optical resolution with D-(-)-tartaric acid:

Post 511856

(Rhodium: "the freebase should be used", Stimulants)

Post 506241

(Rhodium: "chirality of otc tartrate salts", Tryptamine Chemistry)

Post 474569

(bbell: "Hawian baby woodrose", Tryptamine Chemistry)

Post 417270

(pHarmacist: "Sandoz Ltd. LSD synthesis (1946)", Tryptamine Chemistry)

Post 275468

(El_Zorro: "Re: trouble getting yields for LSD", Tryptamine Chemistry)

I recommend this one - so I will retype it:  :)

"This base was dissolved in warm, dry MeOH, using 4 mL per g of product. There was then added dry d-tartaric acid (0.232 g per g of LSD base), and the clear warm solution treated with Et2O dropwise until the cloudiness did not dispel on continued stirring. This opaqueness set to a fine crystalline suspension (this is achieved more quickly with seeding) and the solution allowed to crystallize overnight in the refrigerator. Ambient light should be severely restricted during these procedures. The product was removed by filtration, washed sparingly with cold methanol, with a cold 1:1 MeOH/Et2O mixture, and then dried to constant weight. The white crystalline product was lysergic acid diethylamide tartrate with two molecules of methanol of crystallization, with a mp of about 200 °C with decomposition, and weighed 3.11 g (66%). Repeated recrystallizations from methanol produced a product that became progressively less soluble, and eventually virtually insoluble, as the purity increased. A totally pure salt, when dry and when shaken in the dark, will emit small flashes of white light.

(taken from the LSD-25 entry in TiHKAL...)

And some fun stuff on the topic:

Post 477135

(Mr_Rodgers: "sensitivity of ergolines", Tryptamine Chemistry)

Post 481216

(Rhodium: "An Interview With an LSD Clandestine Chemist", Tryptamine Chemistry)

(took 2 minutes of UTFSE  ;) )

Question to those in the know: is it really D-(-)-tartaric acid which results in crystallization of d-isomers while leaving l- in solution? I begin to wonder because the common naming id D- and L-, but Merck sez that d-tartaric is in fact L-tartaric - I would guess that shulgin referred to D-(-)-tartaric?

Greetz, A


  • Guest
« Reply #50 on: September 03, 2004, 01:08:00 AM »
The procedure works with PyBOP.
No chromatography was used on the woodrose extract, or on the end product, but lysergic acid dimethylamine fine pointy crystals were obtained. WEEEE!

Writeup coming in future.
Legal: Yes, diMETHYLamine was used as lysergic acid diethylamide is a scheduled compound.

Also, about the potassium metal in ether/methanol reflux to isomerize, is that 98% or so yeilds, what's the percentage of lefover iso's? Because, refluxing lysergic acid amide with K to 98%, then precipitating the iso and using K again to get 98% recovery, is like, a 96% overall yeild. Couple that with the high yeilding peptide coupling methods and WHOA, we've got one VERY VERY efficient rxn for what used to be a very difficult and intricate operation.


  • Guest
!! ;^) !!
« Reply #51 on: September 03, 2004, 01:51:00 AM »
NICE! Congrats! No purifying whatsoever? (then the whole last two days spent with studying/searching were more or less unnecessary? Dang, if I'd known that before... :) ). And are you definately sure about the identity of the product? I.e. does it "glow in the dark" (under black/UV light), or does it maybe even emit sparkles when shaken (autoluminescence)? Did your cat/dog/whatever get high on it??  ;)

But don't bee too sure about the legality of LS-dimethylamide..

And another thing google revealed..

About ergot alkaloid content of ipomoea/rivea seeds:

"In 1955 Osmond described personal experiments with Rivea corymbosa seeds and reported that the effects were similar to those of d-lysergic acid diethylamide (LSD-25). He suggested (1957) that the word psychedelic (meaning mind-manifesting) be used as a generic term for this class of substances to refer to their consciousness-expanding and psychotherapeutic function as contrasted with the hallucinogenic aspect. In 1960 Hoffman reported that he had isolated d-lysergic acid amide (LA) and d-isolysergic acid amide from the seed of both Rivea corymbosa and Ipomoea violacea."

I guess Hofmann would've reported the discovery of l-stereomers too. Hm - anyway, reXtalization via d-tartaric is also a good purification method...

Greetz A


  • Guest
NICE! Congrats! No purifying whatsoever?
« Reply #52 on: September 03, 2004, 02:24:00 AM »
NICE! Congrats! No purifying whatsoever?
A simple acid base extraction of woodrose alkaoids and rextallisation gave satisfying crystals.

or does it maybe even emit sparkles when shaken (autoluminescence)?
It was not pure so piezoluminescense wasn't all that great BUT... (see next post)

Did your cat/dog/whatever get high on it?? wink
..The trustable person who performed this rxn says this product is definately active.

But don't bee too sure about the legality of LS-dimethylamide..
It could probably be marked under the analogue act but as far as solid law goes, lysergic acid diethylamide is the only solidly scheduled item. But either way, this is why i wouldn't attempt this rxn, because of the legal reasons. Though if SWIM worked in a proper lab where lysergamide synthesis was needed, BOY OH BOY would this be fun.

Lol, imagine getting a job at a chem synthesis company, and using these techniques. I think the boss would be a bit confused when you got outstanding yeilds, better than thier prepatory methods :P



  • Guest
« Reply #53 on: September 03, 2004, 02:35:00 AM »
Wow! "..The trustable person who performed this rxn says this product is definately active." now that's nice to hear! Hehehe...  :)

It was not pure so piezoluminescense wasn't all that great BUT... (see next post)

 - can't await it! PLZ hurry up, can't wait to see... ;)

I think the boss would be a bit confused when you got outstanding yeilds, better than thier prepatory methods.

Probably - especially when you come up with a lot of hive-powered special procedures to achieve you high yield (how high was it BTW?) - I namely think of "diethylamine from DEET bug repellant"... ;D

(no joke: he would probably be quite impressed and/or ashamed!?)

about the potassium in ether/methanol hydrolysis (do you have a ref for this, too?):
Because, refluxing lysergic acid amide with K to 98%, then precipitating the iso and using K again to get 98% recovery, is like, a 96% overall yeild

I guess you meant hydrolysis of the amine to the carboxylic acid, yielding 98% d-LS? Then the remainder would be d-iso-LS, I would assume - that is 2%. If you really want to bother with that: 98 percent (of starting material) plus (0.98 * 2) percent of the starting material would be 99.96 percent yield of d-lysergic acid from LSA in two steps - assuming that there are no losses during rxn or isolation, which is of course NOT true. So I would just stick with the 98% and call that a very good yield of pure d-lysergic for a one-step hydrolysis... ;)

Greetz, A


  • Guest
Hehe, true about that, Wouldn't bother ...
« Reply #54 on: September 03, 2004, 03:02:00 AM »
Hehe, true about that, Wouldn't bother recovering that crappy product. SWIM got confused when someone in the K-reflux post said something about 50/50 +lysergic acid -lysergic acid, SWIM assumed that the K-reflux would yeild 50/50 of each isomer to a total of 98% yeilds. But if it yeilds 98% of the right isomer then even more WOOHOO!

The synthesizer will synthesise it again im sure, as soon as  he/she is informed of the potassium reflux, i'll make sure she/he informs us of the PyBOP coupling, however this time SWIM has a feeling he'll use PyBrOP (the coupler specifically for dialkyls?) so hopefully there should be an even higher yeild for this.  ;D  ;D  ;D


  • Guest
honestly I don't know, but...
« Reply #55 on: September 03, 2004, 05:34:00 AM »
I don't know if the K/Et2O/MeOH reflux method affects the one or the other chiral center of lysergic or both...

 - but we know that KOH reflux isomerizes at the position characterized as "iso" or "normal" and not at the chiral "d/l"-center of the molecule - at least it is the standard route to change "iso-" to "normal" LS compounds, besides LSA->LS hydrolysis.

It results in d-LS* as well as a smaller amount of d-iso-LS*, but no l-(iso)-LS* - which is maybe produced by some coupling reaction, unless pyBOP or similar is used...
(I hope this was understandable  :) )

So I would think that potassium metal would work much in the same way, but somewhat more thoroughly (i.e. 85% normal/iso vs. 70%(?) normal/iso).

But as said, I'm not sure about whether overall yield or yield of the desired isomer is meant - but the better yield means more of the desired isomer anyway, right? (or would you think it maybe yields 98% of a 70/30 iso/normal mixture? that would be baaad, since after 3 isomerization steps, almost everything would've been converted to iso...)  ;D

How was the yield BTW?



  • Guest
I don't know if the K/Et2O/MeOH reflux method...
« Reply #56 on: September 03, 2004, 05:09:00 PM »
The K/EtO2/MeOH eperimization is useless if you're getting under 3% iso-lsd from tetrabutylammonium hydroxide hydrolysis. K/EtO2/MeOH would only be useful if it hydrolyses lysergic acid amide to lysergic acid in better yeilds than tetrabutylammonium hydroxide, REGARDLESS of isomer proportions (as at the very end, you can run the K/EtO2/MeOH again to convert any iso back to lsd in 98.5% yeilds).

Still trying to get that writeup, person is unavailable at the moment, but it will be posted here as soon as it is recieved.


  • Guest
This just in..
« Reply #57 on: September 03, 2004, 05:24:00 PM »
Pyrrolidide Formation as a Side Reaction During Activation of Carboxylic Acids by Phosphonium Salt Coupling Reagents
Jordi Alsina, George Barany, Fernando Albericio, and Steven A. Kates
Lett. Pept. Sci. 6, 243-245 (1999).

"Pyrrolidide derivatives are observed as unwanted by-products from slow reactions of activated carboxylates with nucleophilic amines, as mediated by phosphonium salt coupling reagents (PyAOP, PyBOP, PyBroP). This side reaction is attributed to the presence of small amounts (e.g., 0.5%, w/w) of pyrrolidine as a contaminant to commercial phosphonium salts, and does not occur when the reagents are crystallized before their use in coupling reactions."

Lysergic acid pyrrolidide is pretty darn impotent compared potency of lsd (1:20th the potency, on rough average), so it is recommended to rextallize the coupler before use.


  • Guest
phosphonium salt couplers are used in tandem...
« Reply #58 on: September 03, 2004, 05:30:00 PM »
Phosphonium salt couplers are used in tandem with a tertiary amine base which abstracts the acidic carboxyl proton.  The generated carboxylate anion attacks the positively charged phosphorous atom, substituting for the benzotriazolyl group.  The benzotriazolyl anion itself acts as a nucleophile at the acyl centre.  In the resulting substitution reaction the OBt ester and a phosphonamide are formed.

Hope this answers why tertiary amines are needed!


  • Guest
« Reply #59 on: September 03, 2004, 06:40:00 PM »
We already know that tertiary amines are there to scavenge the acid remnant of the coupling reagent (resulting in phosphonamide). Now we also know how that it deprotonates the acid, and we know how the reaction works in detail. Nice.

How was the yield the experimenter was able to obtain?