Sciencemadness Discussion Board - piperazine from ammonia?

piperazine from ammonia?

panziandi - 24-8-2009 at 18:24

I believe this reagent was discussed previously on this website, if you use the search engine you may find it.

Reduction of pyrazine would be a good option, following the procedures for reducing pyridine to piperidine. Alcoholic ammonia with 1,2-dichloroethane might be a bit messy. The action of di-sodium ethane-1,2-dioxide on ethylenediamine hydrochloride.

Pyrazine can be obtained from N-(hydroxyethyl)ethylenediamine by thermal dehydrative dehydrogenative cyclization. The precursor can be obtained ethylenediamine and chloroethanol.

kerousel - 24-8-2009 at 19:08

You know you're right search engine would show it, I just realized on wikipedia that this is already an established method of making piperazine...

Here's another question. I know that piperidine can be used to change a OCH3 methoxy group to an OH hydroxy group... would piperazine be able to do this also? It would be nice since piperazine is a lot easier to make than piperidine.

Nicodem - 24-8-2009 at 23:03

Quote: Originally posted by kerousel

Here's another question. I know that piperidine can be used to change a OCH3 methoxy group to an OH hydroxy group... would piperazine be able to do this also?

What are you talking about? Provide a reference!

kerousel - 24-8-2009 at 23:53

Well this is not what I need it for, but this is where I got the idea:
http://www.erowid.org/archive/rhodium/chemistry/codeine2morp...

Nicodem - 25-8-2009 at 00:05

There is no mention of piperidine there. There is described one example of aryl methyl ether cleavage using pyridine hydrochloride. Pyridine hydrochloride is nearly not the same as piperidine. I recomend you to get more familiar with chemical nomenclature. Meanwhile, you can also use ChemDraw to translate IUPAC chemical names into structures and vice versa.

kerousel - 25-8-2009 at 00:24

Oh right pyridine. And this whole time I thought it was piperidine...

Wait a second then I don't understand how it works. The nitrogen probably takes the methyl group and breaks that double bond with the carbon... the carbon now needs a new hydrogen atom... and the O still needs a new hydrogen atom- it doesn't add up!

edit: you know I don't even get how ether cleavage works then. what happens to the pyridine? Idk. I'll probably have to do some more research into this. thanks.

[Edited on 25-8-2009 by kerousel]

panziandi - 25-8-2009 at 05:09

Perhaps, and I am speculating that pyrazine, which is basically pyridine with an extra N in the ring, i.e. an aromatic heterocyclic amine. Could perhaps be used like pyridine if pyridine itself is unavailable. I posted a route to make pyrazine. I think it could be done "OTC" with a little thought and patience.

Ozone - 25-8-2009 at 07:01

Ah. [Piperazine] it will probably do (pyrazine maybe if conditions are oxidizing or if some carbonyl is around to form Schiff bases)...in low yield with a large amount of variously substituted amines (it can add multiple times). Yields will be bad and (I suppose) the mixtures intractable.

I attached the structures for clarification.

Cheers,

O3

[Edited on 25-8-2009 by Ozone]

kerousel - 25-8-2009 at 14:31

Oh alright, thanks. I would think that pyrazine should work for sure, then again I'm not sure exactly how pyridine works to cleave an ether at all.

But at that rate it might just be easier making pyridine from acetaldehyde and ammonia.

[Edited on 25-8-2009 by kerousel]

Nicodem - 26-8-2009 at 00:05

Quote: Originally posted by kerousel

Oh alright, thanks. I would think that pyrazine should work for sure, then again I'm not sure exactly how pyridine works to cleave an ether at all.

Pyrazine has the pKa of 1.1 so it is not like you can make a stable hydrochloride to be used instead of pyridine hydrochloride in methyl aryl ether cleavage.
The mechanism of aryl methyl ether cleavage is SN2. You can find examples and further details about this mechanism in any organic chemistry book, or Wikipedia in case you are too lazy to visit a library. How pyridine hydrochloride works in this cleavage, I explained already in detail in some other thread, so please UTFSE.

Happyer - 23-12-2009 at 05:31

Panziandi- You say 'Alcoholic ammonia with 1,2-dichloroethane might be a bit messy.' What do you mean by this?

Would refluxing 1,2-dichlororethane with alcoholic ammonia for a couple of hours be enough to produce piperazine or would you need pressure?

How about substituting the 1,2-dichloroethane for 1,2-dibromoethane as that is easier to make- pass ethene through bromine liquid.

Eclectic - 23-12-2009 at 07:13

Piperazine can be had cheaply at vet supplier for use as wormer.

Happyer - 23-12-2009 at 10:54

Yes but this is for educational knowledge, i am not interested in obtaining large Qtys as it is listed here in the US.

Nicodem - 24-12-2009 at 00:53

Quote: Originally posted by Happyer

Yes but this is for educational knowledge, i am not interested in obtaining large Qtys as it is listed here in the US.

What are you talking about? Piperazine listed? Listed as what, where and why?
I was told several times that in the USA piperazine salts are just as OTC as here in Europe or anywhere else for that matter.

Happyer - 24-12-2009 at 02:36

I have been told the sale of large quantitys of freebase piperazine or salts are wached due to its possibility of being turned into illict substances.

JohnWW - 24-12-2009 at 03:30

How could one turn piperazine or its salts (most likely hydrochloride) into "illicit substances"? Do you know of any such reactions and products? It does not appear obvious.
PS: I was thinking of "harder" drugs than benzylpiperazine (BZP), which is still legal in many places and only recently criminalized here in New Zealand; i.e. opioids, cocaine, amphetamines, and similar, especially those complying with the "morphine rule" for psychoactivity, i.e. an aromatic ring, attached to a quaternary carbon, itself attached to a chain of 2 or more carbons, with this attached to a tertiary-amine nitrogen.

[Edited on 24-12-09 by JohnWW]

bbartlog - 24-12-2009 at 07:39

Presumably benzylpiperazine is the recreational drug in question (though there are plenty of other closely related compounds that are also psychoactive). Of course this doesn't address the question of whether there is an easy synthetic route from piperazine to benzylpiperazine, but it seems plausible enough (not going to research it right now).

(addendum, edit): The benzylpiperazine synthesis from piperazine is fairly trivial; you can find it in Organic Syntheses.

[Edited on 24-12-2009 by bbartlog]

Happyer - 24-12-2009 at 09:34

JohnWW - Benzylpiperazine is the most obvious drug however there are lots of derivatives which are very trivial to make, hence i am being cautious.

panziandi - 26-12-2009 at 12:34

Well I said "messy" because it is unlikely that piperazine would be the sole product. In fact you are likely to end up with a majority of 1,2-diaminoethane. Other reactions products would be Bis(2-aminoethyl)amine, Tris(2-aminoethyl)amine, 2-Piperazinoethylamine and 1,4,7-Triazacyclononane etc.

I chose 1,2-dichloroethane because, I was speculating, that by controlling the rate of reaction you may favour the formation of the piperazine. 1,2-dibromoethane would react faster, which may favour the formation of some of the other products, mostly 1,2-diaminoethane.

[Edited on 26-12-2009 by panziandi]

DJF90 - 26-12-2009 at 12:57

Its quite easy to see that the first product formed from a mixture of 1,2-dihaloethane and ammonia will be 2-haloethylamine. How this reacts further depends on the proportions of other reagents present.

It can react with a molecule of 1,2-dihaloethane to give bis(2-haloethyl)amine.

It can react with a molecule of ammonia to form 1,2-diaminoethane (ethylene diamine).

These two products can react further with other molecules in solution. Essentially what you get is a mess. The only product I think you can control the reaction to produce is ethylene diamine, done so by adding the 1,2-dihaloethane dropwise to a massive excess of ammonia.

Bear in mind that each amine-halide reaction forms a molecule of HX, so when calculating the quantity of ammonia to use remember to multiply by two to account for neutralisation of HX species formed.

Happyer - 26-12-2009 at 14:39

How do i seperate the piperazine from the other mess?

panziandi - 26-12-2009 at 16:27

Fractionation! Either fractional distillation and/or crystalisation!

B.ps of some of the compounds i think will be encountered:

Piperazine - Melting point 106°C, Boiling point 146°C
1,2-diaminoethane - Melting point 9 °C, Boiling point 116 °C
Bis(2-aminoethyl)amine - Melting point -35 °C, Boiling point 199-209 °C
Tris(2-aminoethyl)amine - Melting point −16 °C, Boiling point 265 °C
1,4,7-Triazacyclononane - Melting point 42-45 °C, Boiling point 110-130 °C/7 mmHg
2-Piperazinoethylamine - Boiling point 218-222 °C

Of course, if you did this on a large scale, you would obtain an acceptable quantity of the desired compound, plus quite a few other useful compounds as by-products.

Eclectic - 27-12-2009 at 06:10

The phosphate salt crystallizes nicely.

Happyer - 23-1-2010 at 09:55

Ok, i have managed to source a product containing 4g of piperazine phosphate, Senna and colours + flavours.
How can i isolate pure piperazine from this? i was thinking product + caustic solution to freebase the piperazine followed by ether extraction, is this right?

turd - 23-1-2010 at 13:58

Come on! You're not expected to go to the next library, but you could at least have read the wikipedia entry on piperazine: http://en.wikipedia.org/wiki/Piperazine

Quote:

Piperazine is freely soluble in water and ethylene glycol, but insoluble in diethyl ether.

Happyer - 23-1-2010 at 14:25

Sorry i must have misread that. any other extraction solvents? DCM, Pet. Ether?

Picric-A - 16-3-2010 at 15:56

Anybody got a simple method of converting piperzine phosphate to piperazine monohydrochloride?

I had an idea, dissolve piperazine phosphate powder an alcoholic NaOH, causing sodium phosphate to precipitate and leaving piperazine in alcoholic solution. feasable?

Thanks

[Edited on 17-3-2010 by Picric-A]

Picric-A - 18-3-2010 at 08:45

I have left over benzyl chloride form my local anasthetic prep and i thought i could make some 1-benzyl chloride.
Looking at org syn the prep:

Quote:

A solution of 24.3 g. (0.125 mole) of piperazine hexahydrate in 50 ml. of absolute ethanol,
contained in a 250-ml. Erlenmeyer flask, is warmed in a bath at 65° as there is dissolved in the solution,
by swirling, 22.1 g. (0.125 mole) of piperazine dihydrochloride monohydrate (Note 1). As warming in
the bath at 65° is continued, there is added during 5 minutes, with vigorous swirling or stirring, 15.8 g.
(14.3 ml., 0.125 mole) of recently distilled benzyl chloride. The separation of white needles commences
almost immediately. After the solution has been stirred for an additional 25 minutes at 65°, it is cooled,
and the unstirred solution is kept in an ice bath for about 30 minutes. The crystals of piperazine
dihydrochloride monohydrate are collected by suction filtration, washed with three 10-ml. portions of
ice-cold absolute ethanol, and then dried. Recovery of the dihydrochloride is 21.5–22.0 g. (97–99%)
(Note 2).
The combined filtrate and washings from the piperazine dihydrochloride are cooled in an ice bath
and treated with 25 ml. of absolute ethanol saturated at 0° with dry hydrogen chloride (Note 3). After
the solution has been well mixed, it is cooled for 10–15 minutes in an ice bath. The precipitated white
plates of 1-benzylpiperazine dihydrochloride are collected by suction filtration, washed with dry
benzene, and dried. The product, which melts at about 280° with decomposition, after sintering at about
254° (Note 4), amounts to 29.0–29.5 g. (93–95%). A solution of this salt in 50 ml. of water is made
alkaline (pH > 12) with about 60 ml. of 5N sodium hydroxide, then extracted twelve times with 20-ml.
portions (Note 5) of chloroform. The combined extracts are dried over anhydrous sodium sulfate, and
the pale-brown oil (Note 6) remaining after removal of solvent is distilled at reduced pressure in a
Claisen flask. The yield of pure 1-benzylpiperazine, b.p. 122–124°/2.5 mm., nD 1.5440–1.5450, is
14.3–16.5 g. (65–75%).

This is realy confusing as it says add 22.1g of piperazine dihydrochloride but then later on it says filter it out! :O is it a catalyst or something? if not can i just miss this out?

So my question is why cant you just add piperazine and benzyl chloride, what the point of the piperazine dihydrochloride and transforming the piperazine to the monohdrochloride? Surly if you use piperazine base you are left only with 1-benzylpiperazine monohydrochloride?

This is a lot more simple, why over-complicate it?

DJF90 - 18-3-2010 at 09:11

Making 1-benzyl chloride from benzyl chloride?! What kind of jibberish is that? Now, if I'm thinking correctly, the piperazine reacts with the piperazine dihydrochloride to form piperazine monohydrochloride (which is a mono-protected piperazine), half of which reacts with the benzyl chloride making your benzylated piperazine (I am assuming this is what you want...) and piperazine dihydrochloride.

If you use piperazine itself, you can get dibenzylation as a strongly competing reaction. Forming the monohydrochloride by addition of acid to piperazine does not work well; hence why they make it the way they do in situ.

For future reference, if something is added to the reaction mixture, its generally for a reason... Omitting it wouldn't be a wise move.

[Edited on 18-3-2010 by DJF90]

Picric-A - 18-3-2010 at 10:39

If piperazine does not work why does the monohydrochloride not work on its own, surly this leaves one NH group open to attack, the other being protected.
ie, start with the monohydrochloride

[Edited on 18-3-2010 by Picric-A]

Satan - 18-3-2010 at 12:37

Quote: Originally posted by Picric-A

If piperazine does not work why does the monohydrochloride not work on its own

It works, that synthesis you pasted is all about it. Maybe you should read it, and don`t trash topic about useful reagent, useful for other things than drugs with questionable value.

turd - 18-3-2010 at 12:44

Well, there is HCl generated during the reaction and the dihydrochloride is insoluble in the reaction mix. That's why you need two molar equivalents of the monohydrochloride. At least that's what I read out of this page:
http://www.erowid.org/archive/rhodium/chemistry/bzp.html

DJF90 - 19-3-2010 at 12:38

What I remember reading was that piperazine, when titrated with one equivalent of hydrochloric acid, forms a product of questionable composition. By forming the dihydrochloride, and mixing this with stoichiometric piperazine, then the monohydrochloride is formed as expected.

Picric-A - 20-3-2010 at 09:48

What about alkylating piperazine hydrogen phosphate (available as Pripsen pipereazine phosphate powder)
Surely this will yield 1-benzylpiperazine hydrochloride and phosphoric acid?

DJF90 - 21-3-2010 at 02:37

I doubt so, as the hydrogen phosphate would require both nitrogens to be protonated, by definition. Therefore they would both be protected. An additional issue with polyprotic acids is that the salts change constitution depending on pH...