Sandmeyer Reaction of GABA to GBL/GHB
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.
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.