The following text is quoted from Reddit user "Spagetiies"´. I lack the chemical expertise to confirm whether this works, but maybe you guys can determine if this is useful!
PS: If anyone would be willing to help me out, Im looking for a way to synthesize amphetamine with mostly homemade utensils, if theres such a thing. Thanks <3
Now to the "unique synthesis"
"An amphetamine synthesis so unique (and un-regulate-able) that it could revolutionize the world of amphetamines."
Alright, I know that a-lot of my titles are "click bait-y (is that a word?)" like this, but this is actually a very unique way to get things done, and goes through intermediates that really have never been used before. I would also like to preface this post by saying, this synthesis is incomplete as not enough research has been done on the topic to conclude whether or not it will work. Some of the reactions are variations of know reactions, but in strange and non-standard ways that result in such a simple synthesis (possibly).
So in my last post I described an enolate synthesis of amphetamines using ethyl acetoacetate. Now while this method has good yields, it has a few problems. First, ethyl acetoacetate doesn't exactly grow on trees [unlike the reagents for this synthesis
] and is quite difficult, possibly dangerous, and low yielding to make. Additionally the halo-benzene also had to be made, which adds one step to every synthesis. Finally, the compound would have to be saponified and decarboxylated to yield P2P, the direct precursor to amphetamine.
Alright now lets talk about why this synthesis is so unique. Amphetamine(s) traditionally has had 3 precursors: ephedrine, P2P, and P2NP. All 3 of these compounds yield your amphetamine through reductions. However there is another precursor that makes amphetamine through an entirely different method, oxidation. This compound is currently known as Alpha-methyl-dihydro-cinnamic acid. You see, if you form the amide of this compound and perform a hoffman rearrangement you get amphetamine. The hoffman rearrangement is a very simple reaction which for all intensive purposes is un-regulate-able.
However that is not the only special thing about this synthesis method. To get our alpha methyl dihydro cinnamic acid (hereafter referred to as AMDCA) we have to make it. Making this compound is much much much more difficult than making P2P if you are going for single additions, but when you do it all in one step you can make this compound no problem (this reaction makes P2P synthesis look like rocket science, while simultaneously being wayyy more complex on the technical side). AMDCA can (possibly) be made from a single reaction with what is know as citraconic acid (and mesaconic acid, which I'm sure if you separate the 2 you could control sterio-chemistry and just make D-amphetamine, though it's unclear which would make D-amphetamine). But now I've just introduced you to a compound that you've never heard of and have suggested a reaction and given no details (how rude of me, I know). Well lets talk about a compound you have heard of, citric acid. Upon dry distillation, at atmospheric pressure, citric acid dehydrates/decarboxylates into itaconic acid. However destructive distillations such as this leave you with an impure distillate, and we still don't have our sweet citraconic acid. Well luckily enough itaconic acid isomerizes into citraconic acid under heating, which means that cleaning and isomerizing your compound all happens in one step (yayyy!!!).
To turn your citraconic acid into AMDCA you are going to need 3 things: An aromatic (any will do, though highly active ones such as indole will work better, though indole specifically will be degraded in the AMDCA -> amphetamine step), a lewis acid (or a strong base, I haven't completely figured that one out), and knowledge that doesn't exist.
Here is where stuff gets very technical so if you don't know a-lot about chemistry you will have a hard time with some of this stuff.
In essence we are attempting to alkylate our aromatic at a position, using our citraconic acid. The formed compound will auto-decarboxylate to form our AMDCA. There are 2 possible methods to do this, and both have different variations to them so I will try to cover as much as I can.
Citraconic acid is quite the molecule, as it contains many different functional groups. The facts we are concerned about are the following: it has a double bond where one side has higher electron density, a higher degree of substitution, is more stericly hindered, and lacks a hydrogen bonded to it. The other side of the double bond is the exact opposite. We want the aromatic to add to the less hindered side for a successful reaction.
If we were to do an acid catalyzed pseudo FC alkylation we could end up with the wrong (structural) isomer due to the markovnikov rule. We could also end up with the correct isomer due to steric effects of the 2 carbonyls, the methyl, and the size of the aromatic.
If we do a base catalyzed micheal reaction we get something weird. No literature I have found discusses using alkenes as the donor. The reaction would also be disfavorable at first glance due to the breaking of the aromatic, though this is only temporary as the alkene on the citraconic acid would be transferred over after the alkylation. We also risk cycloaddion due to both compounds having alkenes (though this is very disfavorable). Its also possible that the citraconic acid just polymerizes before it can react with the aromatic (though this is slowed thanks to that tertiary carbon which is really shitty at polymerization).
Back to the easy stuff:
Overall a reaction setup might look like this: Distill citric acid 2x, add citraconic acid and aromatic to correct solvent (probably just some heptane or ether). Add X (our acid/base/catalyst) and reflux for Y hours. Then perform a workup by adding base/acid (depending on solvent) and filter. Wash with solvent and dry. Add AMDCA to an equa-molar amount of urea and heat until amide is formed (this step could also be done using boric acid catalyst in ammonia solvent). Wash and recrystallize. Add AMDCA-amide to bleach or other hoffman rearrangement oxidant. Collect amphetamine oil, dry over magnesium sulfate, and add to acetone. Bubble in HCl or drop in sulfuric acid to make Amphetamine salt.
This whole scheme seems easy enough, it just has to be confirmed to work.
Possible drawbacks (if it works) include: Only can make primary amines, requires distillation, not compatible with oxidation sensitive substrates, and finally and imo worst of all, this method would encourage economies of scale like never seen before. Citric acid is so unregulated and un-regulate-able that this synthesis becomes practical on large scales. Ammonia/urea and aromatics aren't any better in terms of regulate-ability, and bleaches are make-able by electrolysis of salts. I mean fuck, the only thing in this synthesis that isn't source-able by anyone anywhere ever is aromatics. And if you can't find a single aromatic then you shouldn't be making amphetamine in the first place.
Anyways as usual comments, questions, and criticisms are always appreciated, especially on this post where I don't even know if the reaction would be possible.
The major sources that I used that are not easily searchable are linked here:
Steric Hinderance of Micheal additions
Article about cycloadditon to benzene using a highly active alkene
Article about normal pseudo FC addition to benzene
If anything needs clarification or explanation please ask. I know this post is a bit of a mess but there is really not much of a better way to put all this information in one post.
PS: If anyone would be willing to help me out, Im looking for a way to synthesize amphetamine with mostly homemade utensils, if theres such a thing. Thanks <3
Now to the "unique synthesis"
"An amphetamine synthesis so unique (and un-regulate-able) that it could revolutionize the world of amphetamines."
Alright, I know that a-lot of my titles are "click bait-y (is that a word?)" like this, but this is actually a very unique way to get things done, and goes through intermediates that really have never been used before. I would also like to preface this post by saying, this synthesis is incomplete as not enough research has been done on the topic to conclude whether or not it will work. Some of the reactions are variations of know reactions, but in strange and non-standard ways that result in such a simple synthesis (possibly).
So in my last post I described an enolate synthesis of amphetamines using ethyl acetoacetate. Now while this method has good yields, it has a few problems. First, ethyl acetoacetate doesn't exactly grow on trees [unlike the reagents for this synthesis
] and is quite difficult, possibly dangerous, and low yielding to make. Additionally the halo-benzene also had to be made, which adds one step to every synthesis. Finally, the compound would have to be saponified and decarboxylated to yield P2P, the direct precursor to amphetamine.Alright now lets talk about why this synthesis is so unique. Amphetamine(s) traditionally has had 3 precursors: ephedrine, P2P, and P2NP. All 3 of these compounds yield your amphetamine through reductions. However there is another precursor that makes amphetamine through an entirely different method, oxidation. This compound is currently known as Alpha-methyl-dihydro-cinnamic acid. You see, if you form the amide of this compound and perform a hoffman rearrangement you get amphetamine. The hoffman rearrangement is a very simple reaction which for all intensive purposes is un-regulate-able.
However that is not the only special thing about this synthesis method. To get our alpha methyl dihydro cinnamic acid (hereafter referred to as AMDCA) we have to make it. Making this compound is much much much more difficult than making P2P if you are going for single additions, but when you do it all in one step you can make this compound no problem (this reaction makes P2P synthesis look like rocket science, while simultaneously being wayyy more complex on the technical side). AMDCA can (possibly) be made from a single reaction with what is know as citraconic acid (and mesaconic acid, which I'm sure if you separate the 2 you could control sterio-chemistry and just make D-amphetamine, though it's unclear which would make D-amphetamine). But now I've just introduced you to a compound that you've never heard of and have suggested a reaction and given no details (how rude of me, I know). Well lets talk about a compound you have heard of, citric acid. Upon dry distillation, at atmospheric pressure, citric acid dehydrates/decarboxylates into itaconic acid. However destructive distillations such as this leave you with an impure distillate, and we still don't have our sweet citraconic acid. Well luckily enough itaconic acid isomerizes into citraconic acid under heating, which means that cleaning and isomerizing your compound all happens in one step (yayyy!!!).
To turn your citraconic acid into AMDCA you are going to need 3 things: An aromatic (any will do, though highly active ones such as indole will work better, though indole specifically will be degraded in the AMDCA -> amphetamine step), a lewis acid (or a strong base, I haven't completely figured that one out), and knowledge that doesn't exist.
Here is where stuff gets very technical so if you don't know a-lot about chemistry you will have a hard time with some of this stuff.
In essence we are attempting to alkylate our aromatic at a position, using our citraconic acid. The formed compound will auto-decarboxylate to form our AMDCA. There are 2 possible methods to do this, and both have different variations to them so I will try to cover as much as I can.
Citraconic acid is quite the molecule, as it contains many different functional groups. The facts we are concerned about are the following: it has a double bond where one side has higher electron density, a higher degree of substitution, is more stericly hindered, and lacks a hydrogen bonded to it. The other side of the double bond is the exact opposite. We want the aromatic to add to the less hindered side for a successful reaction.
If we were to do an acid catalyzed pseudo FC alkylation we could end up with the wrong (structural) isomer due to the markovnikov rule. We could also end up with the correct isomer due to steric effects of the 2 carbonyls, the methyl, and the size of the aromatic.
If we do a base catalyzed micheal reaction we get something weird. No literature I have found discusses using alkenes as the donor. The reaction would also be disfavorable at first glance due to the breaking of the aromatic, though this is only temporary as the alkene on the citraconic acid would be transferred over after the alkylation. We also risk cycloaddion due to both compounds having alkenes (though this is very disfavorable). Its also possible that the citraconic acid just polymerizes before it can react with the aromatic (though this is slowed thanks to that tertiary carbon which is really shitty at polymerization).
Back to the easy stuff:
Overall a reaction setup might look like this: Distill citric acid 2x, add citraconic acid and aromatic to correct solvent (probably just some heptane or ether). Add X (our acid/base/catalyst) and reflux for Y hours. Then perform a workup by adding base/acid (depending on solvent) and filter. Wash with solvent and dry. Add AMDCA to an equa-molar amount of urea and heat until amide is formed (this step could also be done using boric acid catalyst in ammonia solvent). Wash and recrystallize. Add AMDCA-amide to bleach or other hoffman rearrangement oxidant. Collect amphetamine oil, dry over magnesium sulfate, and add to acetone. Bubble in HCl or drop in sulfuric acid to make Amphetamine salt.
This whole scheme seems easy enough, it just has to be confirmed to work.
Possible drawbacks (if it works) include: Only can make primary amines, requires distillation, not compatible with oxidation sensitive substrates, and finally and imo worst of all, this method would encourage economies of scale like never seen before. Citric acid is so unregulated and un-regulate-able that this synthesis becomes practical on large scales. Ammonia/urea and aromatics aren't any better in terms of regulate-ability, and bleaches are make-able by electrolysis of salts. I mean fuck, the only thing in this synthesis that isn't source-able by anyone anywhere ever is aromatics. And if you can't find a single aromatic then you shouldn't be making amphetamine in the first place.
Anyways as usual comments, questions, and criticisms are always appreciated, especially on this post where I don't even know if the reaction would be possible.
The major sources that I used that are not easily searchable are linked here:
Steric Hinderance of Micheal additions
Article about cycloadditon to benzene using a highly active alkene
Article about normal pseudo FC addition to benzene
If anything needs clarification or explanation please ask. I know this post is a bit of a mess but there is really not much of a better way to put all this information in one post.
