Sciencemadness Discussion Board

Rhodiums loss of GABA to GHB

Darkfire - 3-1-2005 at 20:44

I found a rhodium mirror which described GHB from GABA. They wayback machine shows no such arctical existing.

Anyways, not that it matters but the GHB has no intent of misuse on any unwilling person.

From what i rember NaNO2 and HCl were used to take the amino to a hydroxy. If anyone has details on this, or any other method of GABA to GHB id be grateful. I cant seem to find the mirror that had the reaction im looking for.

runlabrun - 4-1-2005 at 04:36

Here it is:


Sandmeyer Reaction of GABA to GBL/GHB
by Chromic


Quick introduction:
As other writeups that I have published, this method is 100% OTC. It is awesome for a chemist who wishes to prepare GHB in small quantities and high yields and to do so without directly obtaining any regulated chemicals such as gamma-butyrolactone (GBL) or 1,4-butanediol (BDO). It also avoids the typically low yields seen from the oxidation of tetrahydrofuran (THF). It uses an easy to obtain amino acid, gamma-aminobutyric acid (GABA), and sodium nitrite (NaNO2). It scales very nicely and runs without too much hassle. Not one suspect chemical is used.

The Sandmeyer reaction uses nitrous acid to turn amines into diazonium salts. This reaction, as it applies to turning GABA into GHB, is shown in the first reaction below. Aliphatic diazonium salts rapidly undergo hydrolysis in the presence of water giving off nitrogen gas and leaving a hydroxyl group behind. This is shown in the second step. As a result of these reactions, GABA can be turned into GHB in an easy to perform one-pot reaction.


Running the reaction:
Set up a 2L flask, sitting in ice-water on top of a magnetic stirrer. Now:

Add 3mol GABA (309.4g)
Add 3mol NaNO2 (207.0g)
Add 700ml water (total volume becomes about 1100ml)
Drop in a 1" stir bar and start stirring
Charge a 500ml pressure equalized addition funnel with 3.3mol HCl(aq) (385.0g 31.25%, 334.8ml 31.25%)
Fit the addition funnel with a gas outlet adapter and vent to theoutside
Begin slowly dripping the hydrochloric acid into the mixture. Drip it in at a constant rate of about 1 drop every 2-5 seconds. Speed it up as time progresses and replace the ice as necessary, but do not allow the evolution of the brown poisonous gas to become vigorous. After about one hour after the last drop of acid has been added, there is no need to replace the ice. Once the reaction is done, proceed to extract. (usually 24-36 hours later)


Extracting the goods:
There are many options for this. This is still a work in progress, but after about 20 runs, I came to use this work up. You can use ethyl acetate (EtOAc), chloroform or methylene chloride (dichloromethane aka DCM) to perform the solvent extractions. I have normally used DCM as it's nice since the organic layer drops to the bottom of the separatory funnel.

Setup for a simple distillation.
Distill, throwing out the first 5-10mls, or so, of distillate as it will contain a fair amount of nitric oxides. Distill off as much water as possible, basically until the sodium chloride starts to saturate the aqueous layer and precipitate out.
The remainder of the distillate (approximately 700ml) will contain approximately 1g GBL/10ml.
Treat the remainder of the distillate with NaHCO3 at reflux for 30 mins
Boil with about a 5% volume of activated charcoal (ie 35ml activated charcoal) (compared to the volume of the solution) for 5-10mins.
Allow it to cool and filter, wash the charcoal with distilled water. Save the NaGHB.
With the remainder of the aqueous, extract 5 times with 625ml portions of DCM.
Distill off the DCM (reuse that DCM!).
Distill the GBL (under vacuum if available).
React with NaHCO3 and distilled water and treat with activated charcoal as before.
Typically 375g of NaGHB is made from the solvent extracted GBL and 100g NaGHB from the aqueous distillate. Although conversion is nearly quantitative (as measured by GC/MS), the overall recovered yield is usually about 70%.

For those who don't know how to make NaGHB from GBL using NaHCO3 please read the section on preparation of Sodium GHB using Sodium Bicarbonate (Baking Soda, NaHCO3) found in the GHB faq. Never use unknown grades of NaOH--they may contain toxic heavy metal contaminants.


Notes on procedure:
1M NaNO2/GABA, as the French ref states is far, far too much water. You don't need it. I don't use that much.

It's possible to reduce the water further, down to the minimum necessary to dissolve the NaCl formed, thus avoiding the distillation of the aqueous layer. The trouble with this is that it's not fully practical. All of the GABA/NaNO2 will not dissolve, and you'll see more of an evolution of nitric oxides. The amount of water used is just barely enough to dissolve all of the NaNO2 and GABA to begin with.

If you want to skip the simple distillation (steps 1a-e) and go straight to step 2 (the extraction with the organic solvent) make sure to increase your organic solvent amounts by about 20%. Your yields will go down slightly.

It's possible to used sulfuric acid, however Na2SO4 is not as soluble as NaCl is, mole for mole. You'll need to use more water.

It's possible to use just a little bit less HCl, but hey, a slight excess is always a good idea.

It's possible to dump in a fair amount more HCl to try and push the GBL into the organic layer. It doesn't really work that well though. Yields don't go up.

It's possible to use chloroform or ethyl acetate instead of dcm. Diethyl ether will work as well. Do not try to use anything more nonpolar such as toluene, hexanes or the like. They won't extract much GBL.


Figuring out where the other 30%+ of the yield is going has been frustrating. Perhaps it is staying in the aqueous as free GHB. But do not consume the post-reaction aqueous layer!

The GBL produced from distillation has an putrid sour smell. This is likely trace quantities of butyric acid (the molecule responsible for the smell of rancid butter). It is not toxic in trace quantities and the off-smell and off-taste is cleared by treatment with activated charcoal.

The dose/response curve for NaGHB is exponential. 2g may be a nice buzz, 2.5g an amazing high, and at 3g a novice user could be violently ill, passed out and completely unresponsive. These doses are guidelines. Every person's response will vary. Chronic use of GHB will result in tolerance and physical addiction. Never mix with any other CNS depressants (especially alcohol).

References
Bull. Soc. Chim. Fr.; 1; 88-94 (1989)
GHB Letter to the Alabama Senate Committee on the Judiciary
Acknowledgements
Last, but surely not least, come the thank yous!

First, thank you to the girl who will always have a special place in my heart (and your determination in helping me with my struggles, especially my addiction to GHB and alcohol).

Thank you Rhodium for your hard-work and dedication to your site and the Hive in general. Thank you for pushing me to publish this document. A big round of applause for Steven Fowkes (even though you got your info wrong on MSG -> GBL in one step rxn), Fierceness, Moo, StraightEdge, hCiLdOdUeDn, Roundbottom, Osmium, Bright Star, Methyl Man, Dr_Sister, AB2, Aztec, Hypo, Ueruma, Ezekill, Terbium, Antoncho, Eleusis and Sasha Shulgin for raising my knowledge, awareness and inspiration. :)

Also thank you to the chemists who performed and published Bull. Soc. Chim. Fr.; 1989; 1; 88-94.



Thats what you were looking for right?Have fun.

-rlr

Thank you!

Darkfire - 4-1-2005 at 14:00

:D:D:D

writeup/experience

adroit_synth - 1-2-2005 at 08:24

Thaks runlabrun!

Does anybody have any experience they would like to share regarding this synth?

Perhaps a writeup?

adroit_synth - 1-2-2005 at 08:25

would like some comments b/c all refs for sandmeyer I have encountered refer to converting aromatics

tom haggen - 1-2-2005 at 09:46

Sounds pretty shady to me. I don't really understand how you can say that this synthesis obtains high yields. You start out will 1100 mL of reactants in the beginning of the synthesis, and you end up obtaining only 10mL of GBL? Though I don't doubt this is a good method, the information given here must be taken at face value. For one, you say that this synthesis is 100% OTC. NO2 salts are hardly over the counter, and if they were everyone including myself would be having a field day with preparing DDNP at our own leisure. I have actually gained some new interest in the synthesis of GHB considering that I’m a recovering alcoholic. I have yet to run across this particular route of obtaining GBL. I must say it seems quite promising. I just have a few questions and then I will quit ranting. Where exactly do you find a good source of GABA? Also, what exactly happened to all of those great rhodium sites that were all over the internet a few months ago? Right when I started getting interested in that kind of chemistry those sites disappeared:(
I tried browsing the rhodium thread on this forum to see what happened, but didn't have the patience to pick out the info I was looking for in such a crappy written thread.

[Edited on 1-2-2005 by tom haggen]

runlabrun - 1-2-2005 at 21:47

i have never tried this synth, this was just a copy/paste from rhodium mirror.

NaNO2 is not OTC... correct however its not suspect at all to order, with an appropriate reason as per normal for any order, so OTC in a more liberal sense, just a different counter....

"Typically 375g of NaGHB is made from the solvent extracted GBL and 100g NaGHB from the aqueous distillate. Although conversion is nearly quantitative (as measured by GC/MS), the overall recovered yield is usually about 70%. "
Whats wrong with the yields?

Tom, the 1100mL of reactants includes 700mL of solvent.... ie cannot be used to judge yield?

Tom if you want any rhodium stuff i have several mirrors on my hard drive so just pm me and i can get you what ever you want...

GABA is just as restricted as GBL and 1,4-BD and other associated precursors for GHB, best idea now is oxidation of THF to GBL i belive... in the spirit of the hive... for info UTFSE... lol

-rlr

[Edited on 2-2-2005 by runlabrun]

runlabrun - 1-2-2005 at 21:52

Found this also....
http://www.chemguide.co.uk/organicprops/amines/nitrousacid.h...
Reaction of primary amines with nitrous acid, formation of alcohols.
The only refs for sandmeyer i found were indeed only aromatics, however at this ref it uses primary alkyl amines...

-rlr

Polverone - 1-2-2005 at 22:12

GABA is not restricted in the US. Just look on Google or in the nearest health food store. It's more expensive than THH, but more readily available in reasonable purity too.

tom haggen - 1-2-2005 at 23:08

What exactly is it used for in health food stores? I might go down to the local GNC and have a looksy.

Darkfire - 2-2-2005 at 14:12

Quote:
Originally posted by runlabrun

GABA is just as restricted as GBL and 1,4-BD and other associated precursors for GHB, best idea now is oxidation of THF to GBL i belive... in the spirit of the hive... for info UTFSE... lol

-rlr

[Edited on 2-2-2005 by runlabrun]


GABA is not restricted and is avilible at health stores, not GNC, at least i havent seen it there. You will have better luck at those stores where old lady shop for "organic" foods.

Mumbles - 2-2-2005 at 17:36

quote from a site selling it:


Quote:

GABA, or Gamma-Aminobutyric Acid, is a powerful amino acid that was first discovered in 1883 in Berlin. It is actually classified as a neurotransmitter, which means it helps nerve impulses cross the synapses (gaps) and communicate better. GABA has a great number of positive effects on the nervous system.

In addition, GABA has some startling effects on promoting fat loss. How does this work? GABA stimulates the production of Human Growth Hormone (HGH). It is HGH that has been found in studies to facilitate the metabolism of fats in the body. HGH is also known for its powerful muscle-building effects. Increasing HGH can definitely be a good thing, especially for bodybuilders. HGH tends to decrease naturally with age, so the older you get, the harder it is to lose fat. That's one reason GABA has become so popular.

Other studies have shown that GABA increases the body's sleeping cycle and patients reported much more vivid dreams. Getting a good night?s sleep and obtaining more rest can lead to more energy throughout the day. Not to mention, decreasing fat loss and promoting muscle growth also leads to an increase in energy.


It looks fairly cheap. 100g for about $15-$17.

runlabrun - 2-2-2005 at 21:26

ok my mistake.... i was refering to an old pacia document and subsequent amendment that stated gaba was to be listed as catagory 1....
i now have the new version which i was unaware of.... and it seems they have not put it on there.... strange....

ghb precursor from the local health food store.... hmmmm

-rlr

Darkfire - 2-2-2005 at 21:44

Man in the old days it was the GHB itself in the healthfood stores.

TwistedHick - 3-2-2005 at 00:36

It was sold at the counter a the gym I worked out at in like 90 or 91 . I remeber the fucking cops have him yank it off the self which sucked and the cops that I worked out with thought that it was shit cause they was homicide cops and it helped them sleep

tom haggen - 16-3-2005 at 17:33

Well I went down to the hippie store and had a look around for this fabled precursor. I asked one of the desk clerks if they had any supplements for burning fat by increasing metabolism, and no luck. I will continue on my quest for this precursor because the more I study chemistry the more opportunities I will have to obtain some NaNO2. Anyway if anyone knows a brand name that might help in my quest, I'm open to suggestions. :P

EDIT: I just called my local GNC and it seems they have some in stock. I guess I just wasn't looking hard enough;)

Has Anyone on the forum had first hand experience with this method of GBL synthesis? If so could you tell how your results were.

[Edited on 17-3-2005 by tom haggen]

Darkfire - 16-3-2005 at 18:28

I tryed it with a complete failure. There was no observeable reaction, i think it was poor kno2,. i dont thiunk there was much nitrous acid formed. Also the gaba made a gooey mess, so i just dumped it in an angry tired pissed off way, and went to sleep.

enima - 17-3-2005 at 03:09

The method works as advertised. The product is effectively formed. Usage of the Sodium Nitrite gave good results. The problem with this proceedure lies in the tedious workup, the syntheis is easy enough for anyone to do. (keep in mind that the NO produced needs to be vented OUTSIDE!!!). The large amount of organic solvent needed makes the proceedure frustrating. But 2-3 distillations of the GBL followed by an active charcol treatment usually yields a fairly clean product.

tom haggen - 26-4-2005 at 18:03

I noticed that the MSDS on GBL stated that GBL has a flashpoint of 98C so wouldn't this make it dangerous to distill? Not to mention, GBL has a boiling point of about 206C, so, how would you be able to distill this liquid anyway? Your reaction flask would be bone dry when you were done distilling, and I was under the impression that you’re not supposed to distill chemicals like that. Would you have to add the GBL to a solvent with a higher boiling point and then distill?

[Edited on 27-4-2005 by tom haggen]

runlabrun - 28-4-2005 at 19:43

Flashpoints are the lowest temperatures the substance CAN be ignited with a source of ignition, such as a flame or spark. At temps lower than the flashpoint the substance wont ignite.
The auto-ignition temperature is the one you have to watch out for. Some MSDS list these under or near the flashpoint temp.

-rlr

Mumbles - 30-4-2005 at 13:32

I thought flash point was the lowest temperature that a material could self sustain combustion.

tom haggen - 3-5-2005 at 07:47

I mixed up flash point with the auto ignitoin temp. If you are trying to distill something that has the highest boiling point in the solution, what do you do? Add it to a solution with a component that has a higher boiling point. What i'm getting at here is that I don't want a dry reaction flask.

Misanthropy - 31-7-2006 at 03:58

Any updates to this? Pure GABA can be sourced very cheaply from China by now. Sodium Nitrate is available and cheap as well from your one stop internet auction site. Al-Chymist has cheap DCM & Chloroform.

Come on, let's see some results! What of this distilling issue? Problematic?

[Edited on 31-7-2006 by Misanthropy]

[Edited on 31-7-2006 by Misanthropy]

Organikum - 31-7-2006 at 08:49

I always thought that GBL is best steamdistilled. At 100°C and ph 5-5,5 the equlibrium GBL/GHB is to 80% on the GBL side - the removal of GBL by the steam should push the equilibrium further into the right direction.
IIRC the Ullmann names this procedure as one way to produce GBL.

This should make the workup easy and solvents obsolete.

/ORG

[Edited on 31-7-2006 by Organikum]

Misanthropy - 31-7-2006 at 11:28

Thank you. Dealing with all that DCM was not so attractive. :)

tr41414 - 14-9-2006 at 11:32

I'm actually a bit late... but...

The reaction is well documented on orgsyn...

www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv7p0099

Can you use MonoSodiumGlutamate as a precursor? just one CO2 to be striped of before our final compound... The same reaction should apply for GABA, just adjusting the weight (molar ratio)... I am wondering if that CO2 would get of if someone accidentaly ingested some of the compound (anyone know of psychological activity GBL-g-carboxylic acid)?

There's also a more sophisticated method for producing substituted GBL's, but it is not very economic unless you will produce some ultraGBL analogs (dunno if anything like that exists).

www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv7p0400

Method uses too much of hard to get / watched chemicals, but could be made almost OTC (read notes), you are also limited by volaitility of the olefin used. Someone should try the rxn with styrene (the compound produced should be as useful as plain GBL ;)) and make a report (i don't have GAA needed and i just found out that my beautiful liquid styrene turned into chunk of solid PS:().

jimmyboy - 14-9-2006 at 13:02

just oxidize THF -- far easier to come by

ExothermicReaction - 1-10-2007 at 19:46

So has anyone successfully pulled off a steam distillation? How did it go?

Nicodem - 2-10-2007 at 04:26

Steam distillation or what? Of GBL? It does not steam distill. Please UTFSE before posting! There is a thread exactly on this issue already.

Eclectic - 2-10-2007 at 07:22

Nicodem, please UTFSE before telling people to UTFSE! A search for "steam gbl" returns no hits. And this thread says that GBL steam distills 1g/10ml. I don't know that I believe it, but I think that's what the post is saying.

GBL Steam Distillation Thread

OK, azeotropic distillation, not steam distillation.

Maybe we should be telling people DON'T UTFSE! Use Google site:sciencemadness.org (search terms). :(

[Edited on 10-2-2007 by Eclectic]

Nicodem - 2-10-2007 at 07:29

Yet you found it nevertheless. It is all matter of technique. :P

Eclectic - 2-10-2007 at 07:31

Yea, well I've been doing computer searches for over 30 years. I mean for the sake of the newbies. :P

ExothermicReaction - 2-10-2007 at 08:50

Thanks Eclectic. I can see that its not so simple.

Nicodem : The reason I didn't do an intensive search for the topic is that I was replying to Organikum's comment in this thread where he says :

"I always thought that GBL is best steamdistilled. At 100°C and ph 5-5,5 the equlibrium GBL/GHB is to 80% on the GBL side - the removal of GBL by the steam should push the equilibrium further into the right direction.
IIRC the Ullmann names this procedure as one way to produce GBL.

This should make the workup easy and solvents obsolete."

The only response to his posting was "Thank you. Dealing with all that DCM was not so attractive."

Can you see why I might have inquired further in this thread?

Nice to meet you both. I'm new here, and am not an expert in this field, but its important to me that I gain the respect of the locals. I hope to contribute as I gain knowledge.

maxidastier - 11-7-2010 at 05:32

Quote: Originally posted by jimmyboy  
just oxidize THF -- far easier to come by


Poor yields and not easier :)

jon - 11-7-2010 at 08:57

not to mention thf + oxidizers= bad idea
go to wikipedia and look at the enthalapy of combustion it's off the charts like 3800 kj/mol

it would appear that steam distillation would make this process much easier the main concern is nitrosamines as artifacts of the diazotation.

i think ghb is good if it is used responsibly but in the hands of the "rave scene" it can be disasterous.
what's going on is with that HNO2 it's unstable at room temperature and it disproportionates.
i forget exactly the equation it's a little early i'll get back to it.
but the noX produced forms nitrosamines.
my memory is a little vague but is'nt it true that strong acids decompose NOx compounds?

if i had'nt indulged myself in truckload quantities of mdxx compounds i suspect i would be a little sharper than i am now.


[Edited on 11-7-2010 by jon]

[Edited on 11-7-2010 by jon]

roamingnome - 7-5-2011 at 20:41

my digital merck at least archives monograph 4840

Monograph Number: 4840
Title: g-Hydroxybutyrate
CAS Registry Number: 591-81-1
CAS Name: 4-Hydroxybutanoic acid
Additional Names: g-hydroxybutyric acid; 4-hydroxybutyrate; gamma-hydroxybutyrate; GHB
Molecular Formula: C4H8O3
Molecular Weight: 104.10.
Percent Composition: C 46.15%, H 7.75%, O 46.11%
Line Formula: HOCH2CH2CH2COOH
Literature References: Endogenous constituent of mammalian brain; thought to function as a neurotransmitter or neuromodulator. Biosynthesized from g-aminobutyric acid, q.v.; freely crosses the blood-brain barrier. Prepn of salts: A. Saytzeff, Ann. 171, 258 (1874); C. S. Marvel, E. R. Birkhimer, J. Am. Chem. Soc. 51, 260 (1929). Acute toxicity: B. Bruguerolle et al., Thérapie 32, 375 (1977). GC-MS determn in biological fluids: S. D. Ferrara et al., J. Pharm. Biomed. Anal. 11, 483 (1993). Clinical pharmacokinetics: idem et al., Brit. J. Clin. Pharmacol. 34, 231 (1992). Clinical studies in narcolepsy: L. Scrima et al., Sleep 13, 479 (1990); in opiate withdrawal: L. Gallimberti et al., Neuropsychopharmacology 9, 77 (1993). Review of efficacy in alcoholism: G. Biggio et al., Adv. Biochem. Psychopharmacol. 47, 281-288 (1992). Review of potential role as neurotransmittor: G. Tunnicliff, Gen. Pharmacol. 23, 1027-1034 (1992); of neuropharmacology and abuse potential: R. Bernasconi et al., Trends Pharmacol. Sci. 20, 135-141 (1999).

Derivative Type: Sodium salt
CAS Registry Number: 502-85-2
Additional Names: g-OH; sodium oxybate; sodium g-oxybutyrate
Manufacturers' Codes: Wy-3478; NSC-84223
Trademarks: Somsanit (Köhler); Gamma-OH (Clintec Nutrition); Xyrem (Orphan Med.)
Molecular Formula: C4H8NaO3
Molecular Weight: 127.09.
Percent Composition: C 37.80%, H 6.34%, Na 18.09%, O 37.77%
Properties: Crystals from alcohol. LD50 in male, female rats (mg/kg): 2,000, 1,650 i.p. (Bruguerolle).
Toxicity data: LD50 in male, female rats (mg/kg): 2,000, 1,650 i.p. (Bruguerolle)








but offers scant information of solubility data

see, having read the few threads on the sandmeyer reaction, which is really neat how nitrous acid works on a primary amine
but the debate lingers as to the DCM ,salting out, vacuum or not to vacuum , in other words the workup

so to the post reaction mother liquor I merely added a molar equivalent of KOH in minimum extra water. The color changed slightly to a deeper less greenish yellow. I refluxed this for a bit and started the slow march of distillation. As I went to add vacuum to continue progress some mother liquor belched up into the receiving flask. Serendipitously I evaporated this as a little check of whats going on. I can post a picture but it is a white crust

now i assume this to be a mixed cation Na and K of chloride and butyrate. I now am thinking of ways of further confirming the products of the reaction. Is there some solvent out there that will effect the butyrate and leave the chlorides.

Other then patience this workup is like a breeze so for along.





digitalemu - 31-5-2011 at 08:49

Quote: Originally posted by Misanthropy  
Any updates to this? Pure GABA can be sourced very cheaply from China by now. Sodium Nitrate is available and cheap as well from your one stop internet auction site. Al-Chymist has cheap DCM & Chloroform.

Come on, let's see some results! What of this distilling issue? Problematic?

[Edited on 31-7-2006 by Misanthropy]

[Edited on 31-7-2006 by Misanthropy]



NaNO2 is NOT Sodium Nitrate(NaNO3), it is SODIUM NITRITE(NaNO2). Mixing up the two could lead to bad things as Nitrite is quite a bit more toxic than Nitrate. Careful out there and make sure you know EXACTLY what you are working with.

shulgin - 5-12-2012 at 19:49

hello,
There is one thing I am curious about that rhodium synth that maybe someone could explain to me. after you have added your hcl to the NaNO2/GABA solution, the synth seems to tell you to hit that with NaHCO3 and then pull with the dcm?
That's how I read the synth, but in my mind it does not make sense, it makes most sense to pull the gbl with dcm after the HCl reaction, and then distill off the dcm and hit the gbl with the NaHCO3.
Of course in his workup he refers to three seemingly different remaining distillates, so i'm not really sure of the end procecedure he's trying to convey.
Thanks for your time!

Jesse Pinkman - 6-12-2012 at 13:21

Hi shulgin,
you should first react the GABA/NaNO2 mix with a mineral acid to form the HNO2 and then the diazonium salt, which then converts to GHB.

As I have read from the attached paper, the GHB slowly loses H2O to form the lactone - in this case GBL. This in my opinion why one should wait "usually 24-36 hours" according to the recipe.

Quote:

The rate of this reaction, however, is relatively slow in mildly acidic solutions, and significant conversion of GHB into GBL requires a time scale of several hours (or longer) for solutions of pH 2.0 or greater.


The reverse reaction (hydrolysis of the lactone) is rapid and exothermic.

And finally - I have read in MSDS-s for DCM, chloroform and ethyl ether, that one must work with them always in a fume hood, because of their vapors, which can cause loss of consciousness.
As the attached paper states : "Consequently, ethyl acetate was selected as the most appropriate extraction solvent to recover GHB as a pure residue."

Hope that this answers your question :)

Attachment: Extraction_GHB_Aqueous_Solution.pdf (150kB)
This file has been downloaded 3464 times

bmays - 7-12-2012 at 22:08

Just distill it, atmospheric is fine but all glass is necessary. Discard the first bit, shut it off when the residue starts to burn. Makes a mess of the flask but easier and cheaper then dealing with massive quantities of solvent.

Aaron.j.hard - 14-3-2013 at 05:42


Hi All,
Second Post Please be Kind !!

I was wondering if one could extract GHB / GBL from the reaction distillate by means of a Bisulfite adduct.

Will The GHB / GBL Carbonyl Group enable a SMBS Adduct Like a Ketone ?

1#
Prepare a saturated solution in Water of Sodium Sulfite / Sodium Meta Bisulfite and extract the crude Reaction distillate.

2#
Wash the crude reaction distillate with DCM and then Extract the DCM With a saturated solution in Water of Sodium Sulfite / Sodium Meta Bisulfite.

Filter the adduct and free the product By addition of a base solution such as Sodium Bicarbonate or , Sodium Hydroxide, the Bisulfite is liberated as Sulfur Dioxide.

Just a thought , Thanks.

Hockeydemon - 10-7-2013 at 00:46

Can someone please inform me if I'm misunderstanding the attachment Jesse Pinkman left?

After performing the sandmeyer reaction with GABA, NaNO2, & HCL, and allowing the rxn to rest for 24+hrs. The best way to extract to extract the GHB would be to saturate the post rxn mixture with NaCl, and to add acid until there is a pH below 3 which would convert the vast majority of the GBL to GHB? Then add ethyl acetate, and then distill out the GHB. Then bring the pH back up to 7 with NaOH. Then pass the the GHB/ethyl acetate/H2O through a column of MgSO4 in order to remove any H2O. Then finally allow the ethyl acetate to evaporate.

Or am I just way out of my league here? haha

[Edited on 10-7-2013 by Hockeydemon]

Post sandmeyer rxn GBL/GHB extraction questions

Hockeydemon - 11-7-2013 at 01:00

I have a few questions about this reaction, and the product's extraction. Also I could use some clarification on the attached .pdf file. Please note I have already read every thread I could find using a site specific Google search on this topic.

After the rxn is complete most methods recommend you allow the solution to sit for a minimum of 24hrs. Is this so newly formed GHB cyclizes to it's lactone form? Is there any reason that this is preferable when it comes to extraction?

While distilling ~500mL of post rxn solution at atmospheric pressure ~300mL of crystal clear liquid distills over at 98C.

Everything that I read seems to imply that you cannot distill this over at atmospheric pressure, and you must distill under vacuum because of the high boiling point/azeotrope of GHB/GBL. Yet the distillate that is formed at atmospheric pressure when boiled down to remove the water turns into a wax block. What is this then?
------

Now on to the .pdf attached.

It says that a rxn solution with a pH less than 3 in a saturated solution of NaCl provides the best environment for GHB extraction because the GBL is converted to the free acid form. It also says that ethyl acetate is the most preferable solvent for extraction (yet everyone uses DCM. Why?).

So in theory couldn't you run your sandmeyer rxn, and then saturate the solution with NaCl & make the pH<3. Then simply extract it with some ethyl acetate in a sep funnel? Then bring the pH back up to 7 allowing the lactone to form again. Then you could dry the solution with MgSO4, filter the salt, and evaporate the ethyl acetate? Why would this not work?
------

I get the impression that I'm missing some fundamental concepts in my thought process otherwise I would have been able to simply look this information up & find this. Sorry if this should be in the beginnings section.

Attachment: Extraction_GHB_Aqueous_Solution.pdf (150kB)
This file has been downloaded 985 times

Nicodem - 11-7-2013 at 11:00

Quote: Originally posted by Hockeydemon  
After the rxn is complete most methods recommend you allow the solution to sit for a minimum of 24hrs. Is this so newly formed GHB cyclizes to it's lactone form?

I think the kinetics of this equilibrium are pretty fast, especially under catalyzed conditions (which low pH assures). The 24 h are certainly not for this reason. But why don't you ask the author of the procedure? Whichever procedure that is? You don't refer to any.
Quote:
Is there any reason that this is preferable when it comes to extraction?

Whether the 4-hydroxybutyric acid or its lactone form is preferable for the extraction depends on their corresponding logP. Calculate them for octanol and compare. But in any case, in aqueous solution they are in equilibrium, so you can't have only one or the other, there are always both present.
Quote:
Everything that I read seems to imply that you cannot distill this over at atmospheric pressure, and you must distill under vacuum because of the high boiling point/azeotrope of GHB/GBL. Yet the distillate that is formed at atmospheric pressure when boiled down to remove the water turns into a wax block. What is this then?

I don't know. You formed it, you analyze it.
It's not like you gave us any experimental to do guesswork on. I'm not one of those members that believe hypotheses can be built on non-existing data.
Quote:
It also says that ethyl acetate is the most preferable solvent for extraction (yet everyone uses DCM. Why?).

Perhaps they don't know the logP of the product in CH2Cl2? Or perhaps they have no ethyl acetate or n-butanol? Perhaps they have a surplus of CH2Cl2. Perhaps they don't care for the contamination with halogenated solvents. There are plenty of possible reasons.
Quote:
So in theory couldn't you run your sandmeyer rxn, and then saturate the solution with NaCl & make the pH<3. Then simply extract it with some ethyl acetate in a sep funnel? Then bring the pH back up to 7 allowing the lactone to form again. Then you could dry the solution with MgSO4, filter the salt, and evaporate the ethyl acetate? Why would this not work?

Why would it? Surprisingly enough, many compounds just don't jump out pure out of mixtures, regardless of how strong your wishful thinking is. Just how do you think butyrolactone can be isolated from such a mixture in any effective way without applying fractional distillation? Did you hear about the laws governing the partial pressures of components above their liquid phase mixture? Well, I guess that part of the theory eludes you. Another thing that eludes you, is the irrationality of your belief that the other components, like the crap and the non-volatile side products, would just disappear by itself, without applying a distillation.
Quote:
I get the impression that I'm missing some fundamental concepts in my thought process otherwise I would have been able to simply look this information up & find this.

Yes, you do miss certain fundamental concepts. The problem with fundamental concepts is in that they are fundamental, meaning that you would better learn them before venturing any further into their application. Being ignorant of fundamental concepts is all just fine, as long as you don't try to apply that ignorance in possibly life threatening situations. For example, personally, I'm totally ignorant of nearly all the fundamental concepts that are inhumanly possible in such a wast universe. For this reason, when it comes to experimental work, I rather limit myself into the application of only those concepts that I'm familiar with, or learn the new ones first and apply them later. If none of this is possible, I design experiments with great caution.

Hockeydemon - 11-7-2013 at 15:11

Quote: Originally posted by Nicodem  

I think the kinetics of this equilibrium are pretty fast, especially under catalyzed conditions (which low pH assures). The 24 h are certainly not for this reason. But why don't you ask the author of the procedure? Whichever procedure that is? You don't refer to any.


You're right I should have provided reference. On this Rhodium write up it says 'once the reaction is done proceed to extract (usually 24-36hrs later).' The .pdf attachment says that the free acid form of GHB is unstable, and will readily revert back to it's lactone form after awhile. If the kinetics of the reaction are fast - especially under catalyzed conditions wouldn't the GHB be converting to it's lactone form by waiting?


Quote:

Whether the 4-hydroxybutyric acid or its lactone form is preferable for the extraction depends on their corresponding logP. Calculate them for octanol and compare. But in any case, in aqueous solution they are in equilibrium, so you can't have only one or the other, there are always both present.

Thank you. While we've learned about partition coefficients in school I was always provided with the values to do the math. I was unaware that it was such a simple thing for me to perform. I will have to do this on a few things.

Quote:

I don't know. You formed it, you analyze it.
It's not like you gave us any experimental to do guesswork on. I'm not one of those members that believe hypotheses can be built on non-existing data.

You're right - I just figured doing so would be frowned upon. I have questions about the synthesis, but I did not want to appear to just be asking you how to make it.

Quote:

Why would it? Surprisingly enough, many compounds just don't jump out pure out of mixtures, regardless of how strong your wishful thinking is. Just how do you think butyrolactone can be isolated from such a mixture in any effective way without applying fractional distillation? Did you hear about the laws governing the partial pressures of components above their liquid phase mixture? Well, I guess that part of the theory eludes you. Another thing that eludes you, is the irrationality of your belief that the other components, like the crap and the non-volatile side products, would just disappear by itself, without applying a distillation.

You're right again - that was undoubtedly a really dumb question that I already knew the answer to.

Quote:

Yes, you do miss certain fundamental concepts. The problem with fundamental concepts is in that they are fundamental, meaning that you would better learn them before venturing any further into their application. Being ignorant of fundamental concepts is all just fine, as long as you don't try to apply that ignorance in possibly life threatening situations. For example, personally, I'm totally ignorant of nearly all the fundamental concepts that are inhumanly possible in such a wast universe. For this reason, when it comes to experimental work, I rather limit myself into the application of only those concepts that I'm familiar with, or learn the new ones first and apply them later. If none of this is possible, I design experiments with great caution.


I never had nor have any intention of consuming, or letting anyone consume anything that comes from my experimenting. I'm too cautious/paranoid to try it myself, and too responsible/ethical to risk doing harm to others. I'm acutely aware of my lack of knowledge.

I do appreciate the response to my questions. I'm sure I'll have more after I do some more reading. Thank you.

GHB & GBL via sandmeyer rxn problems?

Hockeydemon - 7-12-2013 at 18:06

I was reading about a person's synthesis online and I can't figure out what is going wrong in their synthesis.
Quote:

The person placed 1 mol of GABA (103g), 69g of NaNO2 (food grade), and 230ml DH2O to a 1L round bottom flask. They then added 115ml HCL (technical grade) dropwise with a rate of ~1 drop/8 seconds with heavy stirring. Once the HCL was fully added stirring continued for ~1hr, and was then transferred to another flask. This procedure was then repeated in order to obtain ~900ml of rxn mixture. The solution was allowed to sit overnight with light stirring to allow the rxn to come to completion (room temperature was ~0 Celsius due to weather). After ~20hr the rxn mixture was placed in a room temperature environment. After the 24hr period the rxn mixture was placed into a 1L rb flask again, and was set up for simple distillation.

The distillate collected was ~400ml of crystal clear liquid. It had a pH of ~6-7, and no noticeable odor. The distillate was brought up to a pH of ~7-8 using NaOH (food grade). This fluid was then transferred to a beaker and boiled down to 100ml and allowed to cool. No solidification occurred so it was further boiled down to 50ml, and cooled. No solidification - the liquid now had a slight yellow hue to it, and a slightly salty taste, and ever so slightly more viscous.

The post rxn mixture was placed in the freezer to precipitate any NaCl, and then decanted off. It was then placed back into a simple distillation until bumping occurred. Then placed back into the freezer to encourage more NaCl precipitation. Once decanted for the final time ~350ml of post rxn fluid was placed into a 500ml sep funnel and washed with EtOAc in 200ml portions 5x times.

The EtOAc was placed into a 1L rb flask with a fractional distillation column. Once all of the EtOAc was collected from distillation ~25ml of dark brown liquid remained. The 25ml was then placed into a micro distillation setup and distilled under vacuum ~5ml of crystal clear liquid was recovered with a pH of ~5.

The discard fluid from the EtOAc washes was now comprised of over 50% salt, and the remaining liquid was a few shades off black.



What exactly is going on in this procedure that would result in no GHB, and very little GBL? I can't find anything wrong with it, and have looked over the erowid procedure to no avail.

Here is the rxn mechanism.





Nicodem - 8-12-2013 at 02:15

Quote: Originally posted by Hockeydemon  
I was reading about a person's synthesis online and I can't figure out what is going wrong in their synthesis.

Provide references when citing! Edit your post correspondingly.

Hockeydemon - 8-12-2013 at 05:53

Quote: Originally posted by Nicodem  

Provide references when citing! Edit your post correspondingly.


I am unable to because the forum that it is off of is something you have to be granted access to. That is all of the information though.. Nvm though someone else worked it out. The guy mistakenly bought L-glutamine rather than gaba powder.

[Edited on 8-12-2013 by Hockeydemon]

Hockeydemon - 11-12-2013 at 02:51

While trying to help that guy on the other forum someone mentioned that Jazz pharmaceuticals is attempting to make an extended release version of Xyrem using deuterium.

This had me wondering about replacing the HCL in the sandmeyer rxn synthesis with DCL. It has the same chemical properties as hydrogen -just heavier. DCL is relatively inexpensive from Sigma-Aldrich, but of course that is not much of an option for most of us. However there is a publication online describing a relatively easy synthesis of DCL.

C6H5OCl + D2O --> C6H5COOD + DCL
C6H5OCl + C6H5COOD --> (C6H5CO)2O + DCL

A Convenient Procedure for the Preparation of Deuterium Chloride
J. Am. Chem. Soc., 1942, 64 (9), pp 2223–2224
DOI: 10.1021/ja01261a054
Publication Date: September 1942

Would there be anything wrong with doing something like this? I read that deuterium pharmaceuticals take ~50% longer to metabolize.



The metabolic pathway using alcohol dehydrogenase would deprotonate the deuterium atom that the sandmeyer rxn left. Wouldn't this all make it relatively simple to make extended release GHB?

I also thought that the the deuterium would exchange protons with the surrounding water in the reaction so you could maybe do the whole rxn in D2O? It appears that placing deuterium on a metabolically labile position is preferable according to this .pdf

Quote:

Substitution of hydrogen(s) at a metabolically labile position with deuterium is a strategy employed to attenuate metabolism Deuteration should have a negligible effect on the biological activity and physical chemical properties of a compound, as deuterium is a naturally-occurring, stable, non-radioactive isotope of hydrogen [12]

A deuterium-carbon bond is more difficult to break than a hydrogen-carbon bond, thus deuteration of a
labile position should slow metabolite formation involving hydrogen-carbon bond scission
[13]



Thoughts anyone?

Zyklon-A - 15-5-2014 at 10:51

I been waiting to try this reaction. I got all the reagents and have done the first half.
I added 15.4 grams of GABA (.15 mols) with 10.4 grams of NaNO3 (.15 mols). This was dissolved in 34.8 mL of water. I then added .16-.17 mols of HCl (aq) drop-wise over a period of three hours.
So now I have a clear solution of GHB with sodium ions, chloride ions and probably a bunch of other stuff. (I don't know exactly what all the reaction products are.) My question is: Do I have to distill it? There isn't much solution there, and yields won't be great if I do. I plan on using chloroform as a solvent - which isn't miscible with water. So would the GHB just go into the bottom chloroform layer or will other crap dissolve too?

GHB appears to be very soluble in chloroform, and sodium chloride is insoluble.

[Edited on 15-5-2014 by Zyklonb]

Nicodem - 15-5-2014 at 10:56

Quote: Originally posted by Zyklonb  
I added 15.4 grams of GABA (.15 mols) with 10.4 grams of NaNO3 (.15 mols). This was dissolved in 34.8 mL of water. I then added .16-17 mols of HCl (aq) drop-wise over a period of three hours.
So now I have a clear solution of GHB with sodium ions chloride ions and probably a bunch of other stuff.

What makes you believe that you have a "solution of GHB with sodium ions chloride ions and probably a bunch of other stuff"? Do you have any analyses?
I'm pretty sure you have nothing but the starting materials there given that you substituted sodium nitrite for sodium nitrate.

Zyklon-A - 15-5-2014 at 11:03

Crap, my mistake. I did use nitrite, not nitrate. That was a typo.
I looked for the actual equation, but couldn't find it, so I'm not sure what other "stuff" might be in there, if any. All I know is there are sodium ions (from NaNO2) chloride ions (from HCl), and NO was given off.

Sorry, I don't know much about organic chemistry, this is one if my first experiments...

[Edited on 15-5-2014 by Zyklonb]

Zyklon-A - 15-5-2014 at 14:38

Ok, well I decided to go ahead and distill it. We'll see how yields go. I guess I should have made a bigger batch, cause I have 500 grams of GABA and 2 lbs of sodium nitrite and lots of hydrochloric acid.

Distillation

hive3 - 19-5-2014 at 07:14

The extraction process is cumbersome and requires large amounts of solvents and pulls over more impurities in my experience. Using steam distillation is much more effective, greener and leads to a much clearer product. See Below:

Synthesis with steam Distillation Purification.
Suggested experimental:
103.1g GABA and 69.0g NaNO2 is added to 1L of water. Stirring is started. 116.7g of 31.25% HCl is slowly added. pH is checked to make sure it's around 4-5 (if not add more HCl). Reaction is run 24hrs with no heating.

The expected yield is 86.1g of GBL. The whole mixture can be distilled to dryness, then 84.0g of NaHCO3 is added to the distillate, refluxed for 30 minutes and boiled down to a reasonable volume and enjoyed responsibly.

>Does GBL steam distill?

Yes, 1 part GBL and 9 parts water seems to do it alright... which is EXACTLY what's called for in the reaction. Distill off the water/GBL and react the distillate with a base (eg sodium bicarbonate which is NaHCO3 which is Baking Soda ).

It's a very efficient way of purifying everything...
If you acidify the solution slightly (pH 4-6), then all of the GHB will turn into GBL eventually in the distillation and steam distill.

I Like Dots - 3-6-2014 at 07:28

Quote: Originally posted by jon  
the main concern is nitrosamines as artifacts of the diazotation.


Ive heard multiple comments on this, but is there any truth to this?
Im guessing the GABA cyclizes (under what conditions?), forming a secondary amine (probably 2-pyrrolidone?) which turns into N-nitroso-2-pyrrolidone.


Just for reference:
Primary Amines with nitrous acid


Secondary Amines with nitrous acid


Steam Distillation of GBL and Conversion to GBH

hive3 - 7-7-2014 at 10:09

Quote: Originally posted by hive3  
The extraction process is cumbersome and requires large amounts of solvents and pulls over more impurities in my experience. Using steam distillation is much more effective, greener and leads to a much clearer product. See Below:

Synthesis with steam Distillation Purification.
Suggested experimental:
103.1g GABA and 69.0g NaNO2 is added to 1L of water. Stirring is started. 116.7g of 31.25% HCl is slowly added. pH is checked to make sure it's around 4-5 (if not add more HCl). Reaction is run 24hrs with no heating.

The expected yield is 86.1g of GBL. The whole mixture can be distilled to dryness, then 84.0g of NaHCO3 is added to the distillate, refluxed for 30 minutes and boiled down to a reasonable volume and enjoyed responsibly.

>Does GBL steam distill?

Yes, 1 part GBL and 9 parts water seems to do it alright... which is EXACTLY what's called for in the reaction. Distill off the water/GBL and react the distillate with a base (eg sodium bicarbonate which is NaHCO3 which is Baking Soda ).

It's a very efficient way of purifying everything...
If you acidify the solution slightly (pH 4-6), then all of the GHB will turn into GBL eventually in the distillation and steam distill.

I would like to point out that the stated 9-1 H2O to GBL ratio is not accurate in my previous post. The following procedure was followed for the distillation and conversion to NaGHB:

On a hot plate with stirring the solution is distilled until salt starts coming out of solution and bumping starts. Approximately 800 ml of distillate comes over. A second 800 ml of H2O is added to the solution and another 800ml of distillate is collected.

200ml of the 800ml first pass distillate is held in reserve. The PH of the distillate is 2.8. 30% NaOH solution is used to bring the ph of the solution to 7.5. The 200ml held in reserve is to correct any overshooting of the PH past 7.5. 9.75g of NaOH neutralizes the first 600ml, and based on this ratio, an additional 3.25g NaOH is added to the remaining 200ml of solution.

The resulting solution is boiled down to approximately 100 ml in a stainless steel pot on a gas burner. This solution is then placed in a small aluminum pan and heated at 170C in a small toaster oven for 1.5 hours when bubbling stops. The pan is allowed to cool and 33.5g of NaGHB is collected as a white soap like block in the shape of the pan. Previously removal of the H2O was attempted over the burner in the pot, but led to significant discoloration of the final product due to uneven heating.
This process is repeated for the second distillation which requires 8.5g of NaOH and yields 26g of NaGBH.

Based on these recoveries, The first distillation recovered approximately 24ml of GBL and the second approximately 19g of GBL. Which is more like a 30:1 ratio of H2O to GBL.

Theoretical conversion of the GBL to GHB on the first run should result in 40g of GBH from 28g of GBL and 13g of NaOH. I was using NaOH that had clumped to make my 30% solution so there was water in the NaOH that obviously skewed my results.


[Edited on 7-7-2014 by hive3]

infinite - 17-2-2015 at 13:18

I want to synthetize Aceburic acid (4-acetyloxybutyric acid)

It is possible that in the reaction of sanmeyer, instead of using water, using glacial acetic acid this compound can form?

Maybe another route is to submit the purified anhydrous NaGHB in a glacial acetic acid reflux

Or maybe Acetic anhydride + butyrolactona , but i think that the yield of this, is very low.

Thanks for the answers