Protium (Hive Bee)
01-15-03 23:02
No 398638
      Preparation of LSD with Thionyl Chloride  Bookmark   

Preparation of Lysergic Acid Diethylamide with Thionyl Chloride

by Protium and Vibrating_Lights


Many methods have been explored in the preparation of lsysergic acid diethylamide from lysergic acid.  The amide to be prepared is a disubstitued amide.   That is, two of the hydrogens on the amide (-NH2 group) have been replaced with ethyl groups.  Amides cannot be prepared directly by mixing a carboxylic acid with an amine.  If the acid were to be simply mixed with the amine, the conjugate base of the acid would be produced, which would not react further while in solution.   If the amine salt is isolated as a crystalline solid and strongly heated, the amide can then be prepared, however, this method would not be convienient due to the high temperatures required for the reaction.   Thus, the most common route in amide preparation is through the intermediate acid chloride.   Many different reagents have been proposed for the conversion to the acid chloride, but we believe that a detailed procedure using thionyl chloride has been previously unreported to the clandestine community.  Herein we report a detailed procedure for the small scale preparation of lysergic acid diethylamide from lysergic acid and diethylamine, using thionyl chloride.


Hotplate/Stirrer combination
Erlenmeyer flask
Separatory funnel
100 mL RB flask
Claisen head with fitting rubber septum
Graduated pipet
Reflux Condenser
Thermometer adapter
Glass tubing
Rubber tubing
Test tube
Moist cotton
Clamps & Stands

3.57  g Lysergic acid
2.0 mL Thionyl chloride
4.5 mL Diethylamine

Ether (anhydrous)
10% aq. NaOH
10% aq. HCl


Assemble the apparatus as shown above in a darkroom.  In the presence of light, water can add to the double bond between the position of carboxide attachment and the aromatic ring.TIHKAL#26  You can omit the syringe for now.  The gas trap shown in the figure will trap the evolution of hydrogen chloride and sulfur dioxide gases.  Warm up the water in the beaker on the hotplate to about 90*C.  Be careful not to boil the water and let the vapor come into contact with the reagents.



Preparation of the Acid Chloride:

Place 3.57 g of lysergic acid into a dry 100 mL roundbottom flask.  Measure 2.0 mL of thionyl chloride into a graduated pipet, and removing the rubber septum, transfer the thionyl chloride into the flask.  Replace the septum.  Make sure that the thionyl chloride does not come into contact with either your skin, or the water in the bath.  Make sure the equipment used is dry.

Begin to stir the mixture lightly, begin circulation of water into the reflux condenser, and gradually heat the mixture to reflux for 30 minutes.

Preparation of the Amide:

Raise the apparatus out of the water bath and allow it to cool down to room temperature.  After the mixture has cooled, remove the rubber septum and pour 25 mL of anhydrous ether into the reaction flask.  Reattach the septum.  Swirl this mixture until a homogenous solution is obtained.

Remove 4.5 mL of ice cold diethylamine and place it into a small erelynmeyer for storage.  Add 8 mL of anhydrous ether to the amine in the flask.  Keep the flask cool while you obtain a syringe.

Draw up the diethylamine/ether solution into a dry syringe and insert the needle through the rubber septum of the apparatus.  Add the solution dropwise over a 10-15 minute period into the roundbottom flask.  At this point you should notice a cloud of diethylamine hydrochloride forming in the flask.  Set the mixture to stir for about 90 minutes.

Remove the rubber septum and pour 14 mL of a 10% aqueous sodium hydroxide solution into the flask in small portions.  Be certain that the concentration is not any higher than this, as the position of the carboxide attachment is very sensitive to acidic and basic pH.TIHKAL#26  Swirl occasionally or set to stir for 15 minutes.  The sodium hydroxide should convert most of the remaining acid chloride to the sodium salt of the acid.  This salt will be soluble in the aqueous layer.  The diethylamine hydrochloride is also water soluble.  Any remaining thionyl chloride should be destroyed by water present in the aqueous sodium hydroxide.  The desired amide is soluble in ether, and it may be helpful to add a bit more at this point.


Remove the gas trap assembly, the condenser, and the Claisen head.  Transfer all the liquid to a separatory funnel.  Shake the funnel for about 2-3 minutes.  The shaking should help the conversion of any remaining acid chloride to the sodium salt.  Allow the layers to separate and then remove then lower aqueous layer, and discard it.  Add another 14 mL portion of 10% sodium hydroxide to the remaining ether layer and shake the funnel for another 2-3 minutes.  Drain and discard the aqueous layer once again.

Now add 14 mL of 10% hydrochloric acid, and shake the funnel for another 2-3 minutes to remove any remaining diethylamine as its hydrochloride salt.  Allow the layers to separate, drain and discard the lower aqueous layer.

Transfer the ether layer into a dry erlenmeyer flask and dry the ether phase with granular anhydrous sodium sulfate.  Decant the ether phase away from the drying agent into another flask.  Evaporate the ether by heating the flask to about 50*C, in a fume hood or with you out of the room.  The crude lysergic acid diethylamide will remain.


The freebase should be dissolved in warm, dry methanol (4 mL/ g lsdTIHKAL#26). This solution should be treated with dry d-tartaric acid (0.232 g/ g LSDTIHKAL#26).  This solution should be treated with EtO2 under stirring until the solution becomes extremely cloudy, and placed into a light proof container inside a refrigerator to induce crystallization.  Further recrystalizations and drying will yeild Lysergic Acid Diethylamine tartrate salt.

This post is dedicated to the late Dr. Timothy Leary

Have fun kids!

01-16-03 00:53
No 398646
      Now thats cookin'  Bookmark   

This write up brings a tear to my eye.Congradulations protium and VL.Id dip my balls in it!tongueIve go the TCwink!NANANA!tongue

The wisest man is deep insane.-GD
01-16-03 01:14
No 398650
      Do you know the yeild??  Bookmark   

Do you know the yeild?? And why wouldn't the lsd form the hcl salt when the ether is washed with 10% hcl solution??
(Chief Bee)
01-16-03 06:36
No 398696
      References ???  Bookmark   

References ???
(Hive Bee)
01-16-03 07:08
No 398704
      Inspiration and study  Bookmark   

Just a modification of a preparation for another similar disubstitued amide to produce our much beloved LSD.  Most of this comes from my brain. I worked through all of the steps myself, and the mechanisms I drew are sound.  The ratios in the procedure are the molar equivalents of the synthesis of N,N-Diethyl-m-toluamide, so the reaction should progress at the same order, considering the identical functional group chemistry, though the reactions will undoubtedly take considerably longer to proceed then the synthesis starting with toluic acid.  I have exaggerated the reaction times to ensure they run to completion.  Most of the steps are just common sense.

With any luck i'll have someone that is able to report yeilds do so in the future, but you can all consider this thread open forum for any trails.  Comments criticisms and suggestions are welcome.  I believe that VL_ is having one of his hyperintelligent lab monkeys work on this currently.  My biggest concern is the effect of the acidic and basic washes on the lsd molecule, but otherwise I am certain of my procedure.  The ratios have been calculated to the best of my mathematical ability, but this is still open for optimization and trial by anyone with the materials and the time.  It may be neccessary to add a bit more diethylamide to compensate for the reaction between HCl/diethylamide in the preparation of the amide from the acid chloride, however the numbers are theoretically sound and all reactions seem to be accounted for.

01-16-03 14:29
No 398831
      decomposition products  Bookmark   

  According to William L. Garbrecht in the'Journal of Organic Chemistry' vol.24 page 368 1959 second paragraph states "attempts to prepare lysergic acid chloride yields only decomposition products".
  The same findings were found by:J.H.Brewster,Journal of the American Chemical Society vol.77,6214(1955). 
(Hive Bee)
01-16-03 14:51
No 398839
      It seems that Dr. Shulgin disagrees with you  Bookmark   

TIHKAL #26, p.492 3rd paragraph

"The earliest synthesis of LSD involved the use of an azide intermediate (the original Hofmann process, 1955), mixed anhydrides with triflouroacetic anhydride (1956) or sulfuric anhydride (SO3-DMF on the lithium salt, 1959), with the peptide condensation agent N,N'-carbonyldiimidazole (1960), or with the acid chloride as the active intermediate with POCl3, PCl5, or thionyl chloride (1963) or just phosphorus oxychloride (1973).  Most methods are faulted due to excessive moisture sensitivity, generation of side-products, or epimerization or inversion of the 8-position carbon to form d-iso-LSD.  The POCl3 procedure is clean and fast, and is the preferred process today for the synthesis of a wide variety of substituted lysergamides." 

(Chief Bee)
01-16-03 15:10
No 398848
      I think...  Bookmark   

Protium: I believe that Shulgin is referring to that the acid chloride is a fleeting intermediate in the reaction, but not one that is isolated, and the other statement refers to the acid chloride being impossible to isolate.
01-16-03 15:19
No 398851
      acid chloride  Bookmark   

my organic chemistry theory leaves alot to be desired. My expertise is in the practical field. Can set-up and operate any synthesis. Just relating info from journals,sorry to upset the apple cart. one question why do i not get the images from your post anymore?
(Hive Bee)
01-16-03 18:20
No 398903
      I appreciate any criticism  Bookmark   

>I believe that Shulgin is referring to that the acid chloride is a fleeting intermediate in the reaction, but not one that is isolated, and the other statement refers to the acid chloride being impossible to isolate.

Well yeah you are right, the acid chloride is not isolated, but fortunately there is no need to do so.  However, the acid chloride is stable enough for the preparation of the amide.  Acid chloride intermediates are commonplace in amide preparation, and there is no reason that I can see why this is any different.  Instead of isolating the acid chloride the amide is prepared directly by treating with diethylamide.

>my organic chemistry theory leaves alot to be desired. My expertise is in the practical field. Can set-up and operate any synthesis. Just relating info from journals,sorry to upset the apple cart. one question why do i not get the images from your post anymore?

Thank you.  I did not mean any offense in my response.  I  appreciate all criticism, especially with research to back it up.  I welcome it.  Unfortunately my web provider is down due to technical difficulties.  The images should return in no more than a couple of days.

(Hive Bee)
01-16-03 22:37
No 398977
      Protium  Bookmark   

Do you know if the monohydrate (lysergic acid monhydrate) can be used in this variation as in the POCl3 peptide synthesis in Shulgin's book?
From what I understand lysergic acid is tough to dry, it requires some harsh conditions, and vacum.
01-17-03 01:53
No 398995
      The acid wash to remove the excess ...  Bookmark   

The acid wash to remove the excess diethylamine doesn't work like with toluamide as stated above. Lysergamides are also amines.
(Hive Bee)
01-17-03 05:48
No 399029
      Thanks Lil  Bookmark   

Of course all of the amides and amines will form salts. If you would remove the ill conceived wash from the procedure and omit the erroneous reagent from the materials list I would be grateful, and let's consider this a collective work wink  Now that I think about it there would also be a lysergic acid chloride hydrochloride, which i'm fairly certain could be isolated.  Hmmmm.  This should pose no problem, just thinking out loud. As for the monohydrate it should substitute fine in the procedure, as the two are interchangable in just about every other synthesis.

* SLAPS FOREHEAD * - What was I thinking?

(Hive Addict)
01-21-03 13:30
No 400250
      Missing part  Bookmark   

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.
well then

He who holds the LSD holds the keys.
01-21-03 16:44
No 400302
      Vibrating Lights Triethylamine or ...  Bookmark   

Vibrating Lights
Triethylamine or trimethylamine?? I guessing triethylamine. And would the extra amine work the same in the synthesis using poc13 and chloroform to soak up any HCl??
(Hive Addict)
01-22-03 17:24
No 400579
      Either  Bookmark   

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.

He who holds the LSD holds the keys.
(Chief Bee)
01-22-03 23:16
No 400689
      Neither "poc13" or "POcl5"  Bookmark   

Neither "poc13" or "POcl5" exists, phosphorous oxychloride is POCl3.
(Hive Bee)
02-06-03 07:54
No 405110
      This reference from Stoll & Hofmann: "The  Bookmark   

This reference from Stoll & Hofmann: "The Ergot Alkaloids" in "The Alkaloids vol. VIII", Manske (ed.), 725-83 sounds like it could have something in common with the above- discussed method:

"A further process, which is used on a technical scale and which, like the azide method, had its origin in the SANDOZ laboratories, employs lysergic acid chloride hydrochloride as the activated form (146, 92).

92. Hoffman, Frey & Ott, Experientia 17, 206- (1961)
146. SANDOZ Ltd., Fr. Patent 1,308,758"

Now, I haven't gotten to the first reference yet, but the second one, the patent, sure doesn't exist on Espace! 1308757 is there, of course, and 1308759 too, but this one they apparently forgot to scan.
(Chief Bee)
02-08-03 18:19
No 405766
      Hofmann article  Bookmark   

Hoffman, Frey & Ott, Experientia 17, 206 (1961) (../rhodium/djvu /hoffmann.djvu)

DjVu Plugin Download (
(Hive Bee)
02-10-03 05:20
No 406187
      That was fast! Do you actually live in the...  Bookmark   

Thanks so much for getting that! That was fast! Do you actually live in the library?

This is gibberish to me, they condense lysergic acid hydrochloride with an ammonium chloride, splitting off ammonia?

So triethylammonium chloride would give LSD? Why doesn't the tributyl amine they use give lysergic acid dibutylamide? Just because it's the freebase? I guess more information is either in the french patent or swiss application mentioned, neither of which are on Espace, or in the promised subsequent article in Helv. Chim. Acta.

This is all very confusing. Sorry for bringing it up.
(Chief Bee)
02-10-03 05:56
No 406193
      It was actually lugh who retrieved the ...  Bookmark   

It was actually lugh who retrieved the article, I just hosted it.

You have gotten it all wrong, they say they are condensing the structure IX with the hydrochloride salt of lysergic acid chloride using chloroform/tributylamine as solvent. There are also talk about making the acid chloride with oxalyl chloride and then something about making the acylazide with NaN3 - some german bee migh shed some light on this.